The story is based on an actual 1950's trip by two university friends, Ernesto 'Che' Guevara (Gael Garcia Bernal) and Alberto Granado (Rodrigo De la Serna). Guevara is studying medicine, Granado biochemistry. They plan to travel from Buenos Aires across the Andes Mountains to Chile, Peru, and, then, to Venezuela. Before too many miles their derelict 1939 motorcycle fails, and the two young men continue by whatever means is available. The journey intent is one of adventure--drinking, meeting women, seeing the world.

The young men do discover South America's impressive natural beauty but more strikingly, their eyes and sensibilities are directed to abject poverty and shocking injustices. These blatant inequities, as well as an extended period of time in a leper colony, contribute to the reframing of their original happy-go-lucky adventure and explain, in part, the impulses that eventually would shape Guevara's role in the Cuban Revolution.