Malaria remains a significant cause of childhood morbidity and mortality worldwide. Drug resistance in Plasmodium falciparum has become widespread in the past 30 years, and in some parts of the world multidrug resistance is common. Chloroquine resistance in Plasmodium vivax has recently been recognized in Indonesia. The mechanisms of drug resistance have been defined for the antifolate antimalarial agents but remain incompletely understood for the quinolines. Judicious use of antimalarial compounds will be essential to prevent the emergence and spread of further drug resistance. The history, geographic distribution, and mechanisms of drug resistance are reviewed, together with current recommendations regarding prophylaxis and therapy.