Six years after the events of Metal Gear Solid 3, Naked Snake's former team, FOX Unit, has broken their allegiance with the CIA and gone rogue. Snake himself is also targeted by the FOX Unit, which sent renegade FOX Unit soldiers to attack and capture him. The game begins with Snake being tortured and interrogated by one of the members of FOX, Lieutenant Cunningham, who's trying to locate the whereabouts of the missing half of the Philosopher's Legacy, with the United States Government having already acquired the other half of the Legacy from the Soviet Union at the conclusion of Snake Eater. Snake is imprisoned in a cell next to Roy Campbell, the sole survivor of an American Green Beret team sent in to investigate the base. Snake learns through Roy that they're on the San Hieronymo Peninsula, the site of an abandoned Soviet missile silo in Colombia.
The two escape and Snake makes his way to a communications base, where he attempts to contact his old CO, Major Zero. Instead, he is greeted by his old FOX comrades Para-Medic and Sigint, who reveal that Snake and Zero are being accused of instigating the revolt and that the only way for Snake to clear their name is to find and apprehend the leader of the rebellion, Gene. To complicate matters, Gene has also convinced most of the Russian soldiers stationed on the base to join their side by simply taking over the chain of command of a former Red Army unit, that was secretly stationed inside the Colombian territory. In order to complete his mission, Snake must persuade enemy soldiers to join his ranks because of the scale of his mission.
Snake and his squad defeat the top members of the FOX unit and eventually they make their way into Gene's guesthouse. Snake learns many things on his way. Cunningham was working for the Pentagon and wanted Snake to push Gene into launching a nuke to Russia to prolong the Cold War. Gene was actually aware of this plan the whole time from information from Ocelot. Gene really wanted to launch a nuke at America to destroy the Philosophers and to make his nation of soldiers, "Army's Heaven". Snake destroys an experimental model of the ICBMG (the Metal Gear model) codenamed RAXA and eventually defeats Gene, destroying the ICBMG itself afterwards. After Gene is defeated he gives Big Boss the funds, equipment, personnel, and all other information regarding Army's Heaven, telling him that one day, he will need to use them. On his return home, Snake is awarded for his actions and establishes FOXHOUND afterwards.
In the end, Ocelot kills the DCI and takes the documents containing the identities of the Philosophers to "end them". After the credits, Ocelot speaks with an unknown man on the phone. Ocelot speaks of using the Legacy to form the Patriots in place of the Philosophers. Ocelot actually wanted the trajectory data of the nuke to point to the DCI so he would bring the documents right to him. Ocelot requests Big Boss to 'join' him and the man on the phone (whose identity is hinted as the "man with the same codename as Null"; and is revealed in Metal Gear Solid 4: Guns of the Patriots) in their new endeavor - becoming the Patriots.
Near the end of the story before the encounter with Gene, Elisa with her ESP abilities told Snake a prophecy, saying "your son will destroy the world; your son will save the world," a prophecy to be fulfilled in the later chapters of the Metal Gear series.
