In no particular order:
Freefall - M/W/F. Among the longest-running strips on the web, and still fresh, especially now that it's aggressively fleshing out the world around the characters. The current storyline (Florence discovers an existential threat to the planet's AIs) is amazingly dramatic while still managing to sidestep Cerebus Syndrome.
Schlock Mercenary - Daily. Richly detailed future world and engaging adventures of a mercenary team therein.
O Human Star - Weekly. LGBTQ sci-fi robot drama, written with great wit and an eye for detail.
Zebra Girl -- Irregular. The titular character deals with alienation, morality and her new powers as her former roommates -- two mages, a werewolf, and a cartoon rabbit -- struggle to keep her from Hell.
Subnormality -- Irregular. One of the most intellectual webcomics out there, sharply drawn with biting satire, long walls of philosophy text, and a man-eating sphynx.
Girl Genius - M/W/F. Online version of the Foglios' excellent comic book. Extraordinary steampunk with a fantastic attention to detail and a larger-than-life feel.
Sorcery 101 -- M/W/F. Urban fantasy with a chain-smoking high-school teacher (who's a mage), his teacher and protector (who are vampires), and his best friend (who's a werewolf with a mage wife and a werewolf kid). Beautifully captures the day-to-day life of people with interesting powers.
Darths & Droids - Su/Tu/Th. "Star Wars: Episode 1" as a roleplaying campaign in a world where the movie never existed, done with screencaps. Owes a lot to DM Of The Rings (see "Concluded" section), and easily meets the same high standards.
Sam and Fuzzy -- M/W/F. The standard adventures-of-a-loser-guy-and-his-talking-"pet" tale seen across a thousand comic strips. However, has made the transition to long-form storylines surprisingly well, with character growth, backstabbing-within-backstabbing, and clever continuity out of what were originally one-off shticks.
Underling -- Tu/F. A superbright kid makes a deal with the devil to destroy the world, and his last-minute change of heart leads to him getting sucked into a land of mythology, and caught up in a rakshasa princess' escape. Nice details like a young rationalist reacting rationally to proof of a god's existence.
Family Man -- Wednesdays. From the creator of "Bite Me," another historical tale: a scholar struggling with his faith amid the Enlightenment, heavily footnoted and well-researched. (Plus werewolves, apparently, though they're taking some time in showing up.)
Order Of The Stick -
M/W/F Irregular. The adventures of a group of AD&D protagonists. Minimal but
endearing art; great occasional potshots at the game rules, and solid plot.
Friendship Is Dragons - T/Th/S. My Little Pony: Friendship Is Magic's pilot episode retold as a D&D campaign, "DM Of The Rings" style.
Goblins - Irregular. Dungeon-crawl comic in which a bunch of goblins become an AD&D adventuring party. Fantastic full-color art; great attention to detail and pacing.
Yet Another Fantasy Gamer Comic (Sometimes NSFW) -- Daily. Life in an AD&D dungeon, (mostly) from the monsters' perspective. Black and white sketches that look like they rolled out of a Disney studio. Contains nudity and suggestive scenes.
Keychain of Creation - M/F. An Exalted comic that started with Order Of The Stick-like art, and transcended it in a surprisingly witty sequence on learning magic.
Guilded Age -- M/W/F. A group of outcasts team up for good ol' sword-and-sorcery adventure. Especially charming are the polite, calm berserker and the wood elf medic.
Over The Air -- Twice Weekly. Silicon Valley life from the inside out — written by one of my ponyfic pals!
Basic Instructions -- M/W/F.
Deadpan observations on life couched as advice, set against unique photographic-style drawings.
nothing comes naturally -- M/F. Whimsically twisted furry comic. Largely manages to read like an in-joke you're actually in on: no small feat.
Awkward Fumbles -- Irregular. An occasionally brilliant (and occasionally just weird) collaboration where word balloons are added to submitted strips. Spiritual heir to "Whispered Apologies."
White Noise -- Mondays. After an alien invasion leaves Earth a shattered mess, a kid with a tail, subtle superpowers, and dreams of an alien beast must live in secret -- and survive the dangerous wastelands and his homicidal pusuers.
Five Glasses of Absinthe (sometimes NSFW) - MTW. Unique, sharp art that uses blocks of color rather than lines, as a wannabe space pirate in an anything-goes future angles for the Big Score. Updates in bursts as each book is finished, rather than continuously.
VG Cats -
Mondays Very Irregular. Obligatory gaming
strip. Infrequent enough that the humor doesn't get stale or too in-jokey; well-illustrated; and wide-ranging.
Speak With Monsters - Irregular. Lore Sjoberg (of Brunching Shuttlecocks fame) does strips riffing off of all the entries in the original D&D Monster Manual.
Edmund Finney's Quest to Find the Meaning of Life -- Sundays. A surreal wandering morality play-slash-travelogue. Thing.
Quantum Vibe -- Weekdays. A young woman takes a new job and gets embroiled in far-flung science and corporate espionage on a madcap trip through the solar system.
Utopiates -- Tu/Th+. Photorealistic glimpse of a near future in which drugs allow people to implant new personalities.
Wondermark -- Tu/F. Old black-and-white illustrations repurposed into a clip-art style strip, heavy on the witty writing.
Runewriters -- Erratic. A transformation mage and his deaf friend get into trouble with corruption spirits. Lovely artwork and imaginative premise.
Prophecy of the Circle -- Mondays. Furry fantasy serial with vivid watercolor art, centering on two races with an old tradition of killing each other, and the kids who seek to shake that up.
Paradigm Shift -- Weekly. A pair of cops investigating brutal killings must contend with mythology come to life -- and then their findings hitting close to home.
Dreamland Chronicles - Weekdays. Per recommendation. Rendered daily strip about a college kid revisiting the all-too-real "fantasy" world of his childhood dreams.
Endtown -- Daily weekdays. Line-art strip about postapocalyptic life that swings between slapstick gags and high drama, and has been pulling off the combination with flair..
The End -- Tu/F. The premise: Two shapeshifting aliens trying to save humans from their impending apocalypse land at a science-fiction convention. Digresses into a lot of Take Thats toward the fandom (including a young psychic pretending to be a dragon Otherkin in order to drive off an Internet boyfriend), but the main storyline promises a lot more.
The Last Mystical Legend Of The Fantastic Fantasy Trigger Star -- Fridays. A deliberately generic fantasy quest strip. Then, within a few strips of the beginning, one of the minions threatening the protagonist dies from being impaled on his own speed lines. Sharp, relentless genre mockery.
Earthsong -- Mondays. Memory-less refugees from a multitude of fantasy worlds find themselves drawn as pawns into a cosmic battle. Mindblowing artwork.
Cuanta Vida -- Erratic. A Team Fortress 2 spy explores the world behind the game, discovering that both sides are being played against each other, and rallies a group for purposes of escape. Heavily shippy; makes it work.
Skin Horse -- Daily weekdays, with weekend special features. A zombie, a talking dog, and a transvestite walk into a bar ... More mad-science goodness from the creator of Narbonic.
Wayfarer's Moon -- Tuesdays. The lives of a half-elf warrior mage, a shapeshifting slave, and an orphaned human intersect in this lavishly illustrated fantasy tale.
Super Stupor -- Erratic. Something Positive artist Randy Mulholland's alternate strip: a dark, adult take on the world of superheroes.
Blank It -- M/Th. Two guys in a featureless void deal
with the world that seems to be emerging from their actions. Seems to have some interesting internal logic
behind the slapstick.
Misfile -- Weekdays. A gearhead guy who gets genderswapped by a slacking angel; a schoolmate that loses two years of her life; and the celestials that get involved. Engaging character drama if you can get past the subtext of "being a woman sucks."
Nobody Scores! -- M/W/F. Continuity-free strip that delights in tormenting its main characters. Snappy art; very easy to pick up on.
MS Paint Adventures -- Irregular/Daily. A parody of text adventure games that quickly descends into farce and evolves into time-traveling, death-cheating, treaty-signing brilliance. The current arc "Homestuck" is slickly drawn, with lots of Flash animations, although "Problem Sleuth" really felt like its creative apex.
Looking For Group -- M/Th. Wisecracking take on a misfit group of fantasy heroes leaving a swath of destruction behind them. Fantastic color art.
Cat And Girl -- M/W/F. Incisive, surrealistic humor.
The twin sister of Bob The Angry Flower, except not raised by wolves.
Theri There - Irregular. A strip by, for, and about Otherkin. Fantastic line art, unique content.
Absurd Notions - Very occasional. Intellectual, good-looking and funny: The webcomic triple crown. I wish there were more of it.
Antihero for Hire -- M/F. A gun-toting vigilante in a future city full of incompetent supervillains faces off with a megacorporation hiding the dark secret of his past.
Afterlife Blues -- M/Th. The tale of a petty criminal and the team of specialists that "hires" him to rescue an AI. From the Miracle Of Science team.
Darken - Irregular. If you've never roleplayed a party of evil characters, this gets the feel of it across well. A lot of intra-party backstabbing has been slowly simmering, and it's closing in on the climax.
One - Daily. But, alas,
on hiatus abandoned. This may be my
substitute now that 1/0 has ended. (Granted, not that Tailsteak has lost any brilliance ...)
Whispered Apologies - Irregular. An occasionally brilliant (and occasionally just weird) collaboration where word balloons are added to submitted strips.
August Jessor - Weekly. Richly colored adventures of a naive but clever young lawman. Apparently untouched since mid-2007.
Spamusement - Occasional. Illustrations of mass e-mail subject lines. Was mostly community-driven for a while; even that appears to have dried up.
Mark of Portent - Occasional. Two friends
get pulled into a console RPG from a mysterious shop and suddenly find themselves replacing the heroes.
1/0 - One thousand strips of a fictional world with no fourth wall. Deep philosophy, a fascinating creator-created dynamic, and emergent complexity. One of the only strips in any medium I've read in its entirety multiple times and still hunger for more. Highly recommended. (Plus, fan art. :))
The Last Days of FOXHOUND - The sort of strip that gives fan homages a good name. Built on the universe of the Metal Gear video games, somehow building a more coherent backstory than the source material. Sharp wit, simple but effective vector art, and the best telepathic wolf ever.
Pastel Defender Heliotrope - M/F. There is so much universe in this comic that it leaks out the sides and spills over the top. Worth reading for the world alone, but the art and characters are good too. Also M/F updates on a side story.
Digger - Tu/Th. Furry fantasy webcomic that transcends genre convention with sheer literary excellence. (And a healthy dose of oracular slugs, library rats and other wondrous oddities.)
DM of the Rings - "Lord Of The Rings" retold as an RPG campaign. Great concept, pulled off with flair, and illustrated with movie screencaps.
Narbonic - Mad science! Geekery! Romance! Talking gerbils! Six years of daily weekday strips and colorful Sunday features. Extremely accessible, but also slyly literate (Antonio Smith, FORENSIC LINGUIST is a hoot; google "Hapax Legomenon" after reading the Victorian space serial; and one critical plot point near the end of the strip revolves around a terribly appropriate literary quotation). Currently rerunning through its archives to add artist commentary.
Minus -- Weekly? Watercolor-painted anime-style comic about a young girl with godlike control over reality. Lovely and poignant; truly hits the mark in examining childhood behavior. Highlights include three beautiful, poignant riffs on hope, sportsmanship, and compassion [might not make sense without the context of the previous strip].
By the same author: Great. The tale of a man's lifelong ambition to serve the best ramen. Memeable, endearing, over the top, and occasionally tongue-in-cheek.
Inverloch - When a young da'kor in a racially fractured world makes a promise to find a lost elven child, it sets him off on a journey to find his past as well. Outstanding artwork and well-realized character growth (though the focus oddly moves away from the central character Acheron as the story progresses). About 750 full-page strips; also apparently collected into five paperback books.
Dominic Deegan, Oracle for Hire - Weekdays. Brilliant fantasy strip with two qualities virtually unknown in the genre: The hero triumphs through superior application of knowledge; and there are more happy, loving relationships than dramatic unrequited ones.
Simulated Comic Product -- Irregular. Half "The Far Side," half sadistic blistering cynicism. This sums it up in one.
Adventurers! - Went from a self-referential parody of computer RPGs to a grand plotline imitating them at their finest. Was going to hit 1000 strips and end, but the author was having so much fun that it stayed on "#999" for months while the storyline wrapped.
A Miracle of Science - Sprawling science-fiction worldbuilding around the story of a cop tasked with keeping the solar system safe from a memetic disease that causes its sufferers to fall into classic mad science tropes and try to take over the world. He teams up with a Martian -- a member of a race linked in a single planetary mind -- and all hell quickly breaks loose.
Shades of Grey -- W/S. "Our quantum age; angels, devils and nothing in between[*]." A heaven/hell war becomes personal for a fallen angel and those around her.
8-Bit Theater - T/Th/S. Probably the best-known 8-bit sprite webcomic out there, but still entertaining on its own merits. It kinda jumped the shark a year or two in, but there are still scattered moments of brilliance.
Freak Angels -- Fridays. A group of young psychics deals with the flooded postapocalyptic world that their own powers brought about. Graphic-novel-quality art by Paul Duffield and the usual brilliance of Warren Ellis. Mature readers.