Malaria continues to be a leading cause of death in the tropics, taking the heaviest toll on children in Africa, where drug resistant Plasmodium falciparum has led to rising malaria mortality. High rates of chloroquine resistance prompted many countries in Africa to switch to alternative therapies to treat malaria. Parasites carrying mutations that render them chloroquine resistant may lose their survival advantage with the removal of chloroquine drug pressure. Alternatively, organisms may have undergone compensatory mutation that provides a survival advantage even in the absence of drug pressure. Decreasing drug resistant malaria has been reported following discontinuation of antimalarial drugs. However, most such reports are limited by the incomplete removal of chloroquine drug pressure, unreliable in vitro susceptibility assays and/or small, poorly described study populations. In Africa, Malawi was the first country to switch from chloroquine to sulfadoxine-pyrimethamine for the first line treatment of malaria. An effective campaign to end chloroquine use provided an excellent opportunity to study the natural history of drug resistance following the reduction of drug pressure. The finding that drug resistance decreases with the removal of drug pressure could provide a new paradigm for malaria treatment policies in Africa.