Unlike previous adventures, Andrew Hussie is employing the readers' commands to tell his own complex, planned tale; however, he’s stated he still makes things up as he goes and gets ideas from forum discussions. Andrew has said that Homestuck's basic premise was inspired by games like The Sims, Spore, and EarthBound.

As described on the MSPA website, Homestuck is ‘a tale about a boy and his friends and a game they play together’. On his 13th birthday, John Egbert receives the latest computer game, an immersive simulation game called Sburb Beta. Working with his friend Rose Lalonde, they discover it is a game that allows the players to manipulate their reality.

A startling revelation comes, however - an apocalyptic meteor shower is beginning to destroy the world before their very eyes. However, the game gives them tools to escape their fate. John, Rose and their friends Dave Strider and Jade Harley work together to flee the apocalypse and enter a new dimension called the Incipisphere. The Incipisphere is a world of ‘warring royalty in a timeless expanse’, where the forces of Prospit and Derse struggle for dominion over the realm of Skaia in the chess-patterned Battlefield at its center. Their primary guides are the spirits known as Kernelsprites. They must fight against the monsters of the dark kingdom, controlled by the Denizens, and free the Consorts of the four planets circling Skaia. They must master the inventory system called the Sylladex, and master the alchemy system the game provides.

John, Rose, Dave and Jade slowly learn of their roles as the Heir of Breath, the Seer of Light, the Knight of Time, and the Witch of Space. They must all undertake personal journeys and come to terms with their relationships with their Guardians. They learn they must pass the Seven Gates, reach Skaia, and stop the Black King and Black Queen from destroying Skaia in an event called the Reckoning. However, it’s said that Skaia would buy the kids time by creating defense portals that would redirect the meteors to another place in paradox space – Earth. Some of these meteors are to ‘seed’ laboratories like the Skyship Base on Earth, and carry Exiles – former members of the two kingdoms – to the year 2422, long after the apocalypse, for them to repopulate the Earth. Others spawn anomalies like the Frog Temple, and others become the meteors that hit the kids’ houses in the first place. However, another revelation happens as John eventually reaches a laboratory in the Incipisphere’s outer meteor belt called the Veil, where he uncovers a mysterious ectobiology machine. John accidentally facilitates the kids’ and their guardians’ own existences. They are sent back to the past on meteors during the Reckoning too, to set in motion the entire chain of events.

However, things begin to go wrong, as a weapon Jade tries to give to John accidentally ends up in the hands of Jack Noir, the nefarious Archagent of Derse. He commits double regicide against the monarchs of Derse, and becomes the Sovereign Slayer, wreaking destruction wherever he goes – something never intended to happen in the game.

Meanwhile, time wears on and the kids learn to wake their dream selves up. However, on their quest to grow up and fill into their hero roles, they also stumble upon signs that their mission will end in disastrous failure if they continue on their path. They also learn that they are not the only group of people playing the game. Countless other sessions of players, on other planets in other dimensions, also exist. They begin to be contacted by the twelve Trolls – players from another planet and another dimension, who played a session of Sburb (or, as they called it, Sgrub) long ago in the past. Many aspects of their session were similar, with their own twelve-planet Incipisphere, their own Exiles and more. These twelve managed to win their game, and discovered the ultimate purpose of Sburb – the purpose of Sburb is to create new universes. And, they did – it turns out that the Kids’ home universe was created by none other than the Trolls.

However, something went wrong, and an indestructible, omnipotent demon was unleashed into their game, which is said to have dire consequences for both the Kids and the Trolls. Before the Trolls could gain access to the new universe, they were stopped by a rift in the space-time continuum called a Scratch. It was later revealed that this demon was actually Jack Noir who under unknown circumstances got into the session of the trolls and prevented them from winning the game. The trolls soon got in touch with the Kids, and now they are begrudgingly attempting to help the Kids, learning of things like the First Guardians of Earth and Alternia, and the Green Sun. It is said they will work together to create the Scratch in the future to escape their fate, but what happens beyond the Scratch is anyone’s guess.

Many recurring elements are featured in the comic, like chess, amphibians, meteors, the number 413, a certain bunny and more. With the game of Sburb seemingly having such a profound level of control over reality, all of these factors will undoubtedly add up to a grand adventure the likes of which no one has ever seen. Will our heroes find a way to break this cycle of apocalypses and return balanced order to reality? What the future will hold, we can only guess.

The comic has a sub-comic, the totally rad Sweet Bro and Hella Jeff, written by the character Dave Strider.