After the comet had passed, all the planet's researchers concluded its strange green dust had no effect on the world. None noticed that tiny plants and fungi were acting strangely. Mushrooms, cacti, kudzu and other formerly-normal plants had awoken to full consciousness. Tribes quickly formed among the various mushroom species: the primitive Boletes, the aggressive Amanitas, and the inventive Morels. With nations formed, war inevitably followed.

Mushroom Men – The Spore Wars, picks up during the escalating war between the mushroom factions. The world is more hostile and combat is more complex. New tools and weapons are developed to assist in the escalating battles. The player takes on the role of a misfit and unexpected hero destined to bring about the conclusion of the Spore Wars while solving his own personal quests. The game presents the story simply, providing a strong sense of continuity to the single-player game without intruding on the gameplay.

Mushroom Men and their other sentient neighbours neither speak nor understand human languages such as English. But they still communicate, and to the human playerit sounds like mumbling.