Resistance of Plasmodium falciparum to chloroquine has emerged in the late 1950s and has now conquered the large majority of areas where this species is endemic. Resistance to alternative drugs has already occurred in several parts of the world and has become a particularly serious problem in Thailand. Emergence and spread of resistance are the result of interactions between parasite, humans, vector and drugs, enhanced by particular ecological features. The control of malaria transmission by means other than drugs would probably curb the propagation of resistance but current health care policies offer only limited prospects for the reactivation or implementation of systematic malaria control before the potential of the affordable antimalarials has been exhausted. In this article, Walther Wernsdorfer considers the epidemiological factors associated with the development and spread of drug-resistant malaria.