An ichorous green meteor plummets through the Earth's atmosphere, fracturing and showering the earth with glowing green space dust that affects all forms of life nearby. Some plant life - mushrooms and cacti - acquire sentience while, the meteor twists and mutates other life forms, transforming insects and animals into semi-intelligent, warlike communities.

The story of Mushroom Men is told in Acts, each Act occurring in a completely unique environment. Each version of the game (DS and Wii) tells different portions of the history of the Mushroom Men universe. The DS and Wii versions are completely different stories from one-another. The DS version, Mushroom Men – Rise of the Fungi, is the first release and shows the development of the Mushroom Nations, starting very early in Mushroom Men history. The early days of the Mushroom Men were simpler times as the Mushroom Men were just learning to walk, communicate and interact with their world. As the Mushroom Men learn how their world works, they take the player with them, developing their skills, abilities and histories up to the start of the Spore Wars.

The Wii title, 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.

Wii

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.

Some among the four Mushroom Men tribes believe that the secret to winning the Spore War lays in uncovering the facts about the Mushroom's origins. As the myth states, the Mushroom who discovers the truth of this mystery is promised the power to change the entire course of evolution, putting the Mushroom species at the top of the evolutionary ladder. The tribe that claims this prize can reshape the world any way they see fit. The Amanitas Empire and The Lepiota Order see the myth as a chance to not only defeat the other nations (the Bolete Tribe and the Morel Brotherhood) but also wipe out all of their enemies and put their tribes at the forefront of terrestrial evolution.

Even while the Spore War rages, a great quest amongst all four tribes begins: a race to uncover the truth and reshape the evolutionary course of the Earth. As for the humans, they continue to bumble their way through the world completely unaware of the diminutive forces rising against them. Pax, a Bolete mushroom from the outskirts, doesn't yet understand his place in the events to come. He'll have to learn, and fast, that he’s unwittingly been thrust into the middle of this situation.