A team of researchers has identified numerous mutations that allow the malaria-causing parasite Plasmodium falciparum to become resistant to treatment. Knowing the identity of genes that impart multidrug resistance is important for the design of new drugs, and for understanding how existing therapeutics can lose their efficacy in clinical settings. Worldwide, hundreds of thousands of people die from malaria each year, and the recent evolution of drug-resistant strains of the parasite in Southeast Asia is now intensifying the need for novel treatment options. To better understand how the parasite develops resistance to different drugs, Annie Cowell et al. performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 groups of compounds. In 83 key genes that are associated with drug resistance, the researchers identified hundreds of changes that could be mediating this effect, including repeated genetic coding or mutations resulting in altered proteins. The team then used clones of well-studied P. falciparum parasites and exposed them to the compounds over time to induce resistance, monitoring the genetic changes that occurred as resistance developed. Remarkably, they were able to identify a likely target, or resistance gene, for every compound. In particular, Cowell et al. identified mutations that repeatedly occurred upon individual exposure to a variety of drugs, meaning that these particular mutations are likely mediating resistance to numerous existing treatments. Jane Carlton provides more context in a related Perspective.