Guides are NPCs who give players special Missions that reward them with Guide Rewards, Taros, and Fusion Matter.

In the Future, players' guide is Computress. Until players leave to go to the past, Computress will remain their guide and cannot be changed. Upon entrance to the past zone, each player is given a choice of choosing one of four guides: Edd, Ben, Mojo Jojo, or Dexter. If the player does not like a current guide, the player may change the guide for a new one at a Guide Changer for a small fee. There are Guide Changers found in various places in the Cartoon Network Universe; players can also change guides by talking to one of the guides directly. Players may do only one guide Mission at a time, just as with Nano missions.

Each Guide has a unique story arc and special weapons and clothing. These items may only be used as equipment when players have selected the particular Guide corresponding to those items. Once players change a Guide, these unique Guide items and weapons must be returned to the player's general inventory. If players re-engage the discarded Guide later, they can use those items again. Guide weapons and defensive clothing include some of the best items in the game. Among these are the types of clothing that NPC groups like Urban Rangers and Plumbers wear, as well as clothing based on the Mission handler, e.g..,  Samurai Armor from Samurai Jack and Black Knight Armor from Billy. There is also clothing representative of various CN shows, such as Ben 10's Sumo Slammer Armor and Code Name: Kids Next Door's Battle Ready Armor.

None of the guides (except Dexter and Computress) have survived in the Future zone.

Trivia

• According to FussionFall Retro Gamemaster Przzyfied , during the early planning stages of FusionFall, completing guide missions would've been the method by which players would fight fusions and receive Nanos. Every guide would've given the player a total of 9 Nanos by the end of their mission line, and the guide you picked would've determined the story for each playthrough of the game.
• If you change your guide while wearing a piece of another guides set, you are still allowed to wear it, but its stats will not added to your character.