Molecular epidemiological investigations have uncovered the patterns of emergence and global spread of Plasmodium falciparum resistance to chloroquine and sulfadoxine-pyrimethamine. Malaria parasites highly resistant to chloroquine and pyrimethamine spread from Asian origins to Africa, at great cost to human health and life. If artemisinin-resistant falciparum malaria follows the same pattern, renewed efforts to eliminate and eradicate malaria will be gravely threatened. This paper, adapted from a talk given in honour of Professor Malcolm Molyneux in Liverpool in September 2008, reviews the rise and fall of clinically important forms of drug-resistant falciparum malaria and considers how lessons learned from studying the evolution of drug-resistant malaria can be applied to efforts to prevent and deter resistance.