Artemisinin-based combination therapies (ACTs) are the recommended treatments for Plasmodium falciparum malaria in all malaria endemic areas of South America. Resistance of P. falciparum to the artemisinin drugs has already been detected in the Greater Mekong subregion of Southeast Asia and would represent a major setback to malaria control efforts if it were to develop in or spread to South America. Although artemisinin resistance has not been confirmed in the Americas, the interior of Guyana, Suriname, and French Guiana and bordering areas of Brazil and Venezuela (together known as the Guiana Shield) share many characteristics with the Greater Mekong subregion that increase the risk for selection of resistant parasites. These characteristics include higher levels of transmission of P. falciparum than in the rest of the Amazon Basin, highly mobile populations, ready availability and widespread use of a variety of antimalarial drugs of questionable quality, including artemisinin monotherapies, and lack of access to and use of formal malaria diagnostic and treatment facilities. Since the emergence of artemisinin-resistant P. falciparum in the Guiana Shield could seriously jeopardize malaria control efforts throughout South America, prevention of multidrug resistance including ACT resistance be seen as one of the highest malaria control priorities in the Region.