Chloroquine resistance in a P. falciparum cross maps as a Mendelian trait to a 36 kb segment of chromosome 7. This segment harbors cg2, a gene encoding a unique ∼330 kDa protein with complex polymorphisms. A specific set of polymorphisms in 20 chloroquine-resistant parasites from Asia and Africa, in contrast with numerous differences in 21 sensitive parasites, suggests selection of a cg2 allele originating in Indochina over 40 years ago. One chloroquine-sensitive clone exhibited this allele, suggesting another resistance component. South American parasites have cg2 polymorphisms consistent with a separate origin of resistance. CG2 protein is found at the parasite periphery, a site of chloroquine transport, and in association with hemozoin of the digestive vacuole, where chloroquine inhibits heme polymerization.