The plot begins with Sam Fisher undergoing unfamiliar spy techniques training in the streets of San Francisco in a joint exercise between the Central Intelligence Agency and Third Echelon. Fisher is soon after summoned to Maryland by Colonel Irving Lambert. Turns out, Sam's estranged brother, Peter, has been found barely alive off the coast of Greenland. Sam is told that Peter has developed a strange disease and has few days to live. It is soon revealed that Sam's brother died of poisoning caused by plutonium hydride-19, or PuH-19. This deadly powder is 1,000x finer than flour and is capable of wiping out New York's entire population with just a cup's worth of the chemical.
Although driven at first solely by vengeance, Sam Fisher soon realizes that Peter's death should be the least of his worries as a network of KyrgyzIslamic fundamentalists have toppled the moderate government of Kyrgyzstan and, with the help of the North Korean government, have devised the ultimate antidote against the pervasive influence of the West and its technology: they will try to mutate a species of petroleum-eating Chytridiomycotafungus into a strain capable of making the whole world's oil supply disappear, a threat Fisher and Lambert continually refer to as Manas, in reference to the Kyrgyz epic poem. In order to do this, the terrorists snatch some of the world's leading scientists and force them to cooperate. Sam gets his final lead by tracking one of the abducted scientists in a search that will lead him to a place such as the streets of Montreal, Quebec, Canada, an isolated Kyrgyz community in Cape Breton Island, the Great Rift Valley, Kenya, Pyongyang, North Korea and a Kyrgyz complex hidden in the Tian Shan mountain range.