Firestorm takes place directly after the events in Tiberian Sun. The Brotherhood of NOD, reeling from the loss of Kane, is once again divided and struggling against the persistent attacks of the Global Defense Initiative. CABAL, the artificial intelligence entity that played a critical role in Kane's plans during the second Tiberium War, is now offline, in effect creating a logistics nightmare for the Brotherhood.

Power-hungry generals are all vying for control of NOD, yet each has a markedly different opinion on how to reclaim the Brotherhood's status as a viable threat to the GDI. Kane's Cairo temple, like his dreams, lies in ruins, swarmed by GDI scientists searching for clues that'll help them stop the onslaught of a more insidious enemy: Tiberium itself. Named after the Tiber River where it was first discovered, Tiberium is now rapidly spreading across the planet like a virus, destroying all ecosystems and life-forms that stand in its destructive path. Tiberium was introduced to Earth by a meteorite and was at one time seen as a miracle resource: limitless in its abundance and harmless to others. Its disastrous effects quickly came to light, however, and the toxic crystal has all but leeched the planet's entire supply of naturally occurring metals and minerals. Life-forms that aren't instantly killed by exposure to Tiberium are affected on their genetic level and slowly mutate into hideous, almost alien, creatures.

Even the oceans have become infested with Tiberium, making sea voyages not only difficult, but lethal as well. Desperate to find a way to stem Tiberium's alarming rate of growth, the Global Defense Initiative has raided the now-destroyed NOD temple in Cairo in search of the Tacitus, an alien artifact that could explain the origins of Tiberium. Kane had been using the Tacitus to mutate his troops in bizarre Tiberium experiments and as a result was able to successfully genetically engineer his cyborg units. The GDI now hopes that the same artifact responsible for Tiberium's destructive march across the planet will be able to stop the crystal's spread and save humanity from extinction.