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The setting is in the inner world of a computer system known by its inhabitants as Mainframe. It was deliberately chosen due to technological constraints at the time, as the fictional computer world allowed for blocky looking models and mechanical animation. Mainframe is divided into six sectors (moving clockwise): Baudway, Kits, Floating Point Park, Beverly Hills, Wall Street, and Ghetty Prime. The names of Mainframe's sectors are homages to famous neighbourhoods, mostly in New York City or Los Angeles. However, the Kits sector is named for Kitsilano, a neighbourhood in Vancouver, British Columbia, Mainframe Entertainment's home city. Also, Ghetty Prime is a reference to Frank Herbert's Dune, as Giedi Prime is the home world of House Harkonnen, the villain in the first book of the series. Mainframe is populated almost entirely by binomes, little creatures that represent either 1s or 0s, as well as a handful of Sprites who are primarily humanoid creatures of more complex design and are the main characters of the series.

The first season of ReBoot was highly episodic, with each installment being a self-contained episode. Most of the episodes established characters, locations, and story elements, such as the gigantic "Game Cubes". When "The User" loads a game, a Game Cube drops on a random location in Mainframe, sealing it off from the rest of the system and turning it into a "gamescape". Bob frequently enters the games, "Reboots" to become a game character, and fights the User's character to save the sector. If the User wins a game, the sector the Cube fell in is destroyed, and the Sprites and binomes who were caught within are turned into energy-draining, worm-like parasites called Nulls.

The second season featured an extended story arc that began with the season's fifth episode, "Painted Windows". The arc revealed that Hexadecimal and Megabyte are siblings, and that Megabyte referred to his pet Null, Nibbles, as "father". It also introduced an external threat to Mainframe, "the Web". A creature from the Web entered Mainframe from Hexadecimal's looking glass (which was shattered by Mike), bonding with her. Mainframe's nulls covered her to form a monster known as "Nullzilla". The protectors of Mainframe defeated Nullzilla and neutralized Hexadecimal. The Web creature located Megabyte, took him over and forced him to merge with Hexadecimal, forming a destructive super-virus called Gigabyte. Gigabyte was eventually neutralized as well, but the Web creature escaped into the bowels of Mainframe, where it began stealing energy to stay alive. When the Web creature was cornered as Bob and the others investigated, it escaped Mainframe and opened a portal to the Web. The protectors of Mainframe had to team up with Megabyte and Hexadecimal to close the portal, but when they defeated the Web creatures that had entered the system, Megabyte betrayed the alliance, crushing Bob's keytool, Glitch, and sending him into the Web portal before closing it.

For the show's third season, there was a marked improvement in model and animation quality due to the advancement of Mainframe's software capabilities during the time between seasons. Subtle details, such as eyelashes and shadow, as well as generally more lifelike sprite characters, were among several visual improvements compared to previous ReBoot episodes. In addition, the show shifted their target audience to children aged 12 and older, resulting in a darker and more mature storyline. After severing ties with ABC following the second season, the show actually reached a greater number of households through syndication.