Abstract
Simple genetic changes that correlate with drug resistance are used routinely to identify resistant pathogens. These "molecular markers" have usually been defined long after the phenotype of resistance was noted. The molecular changes at the "end game" reflect a long and complex evolution of genetic changes, but once a solidly resistant set of changes assembles under drug selection, that genotype is likely to become fixed, and resistant pathogens will spread widely. Artemisinins are currently used worldwide to treat malaria caused by Plasmodium falciparum, but parasite response has diminished rapidly in the Mekong region of Southeast Asia. Should artemisinins lose potency completely and this effect spread worldwide, effective malaria treatment would be almost impossible. The full range of modern methods has been applied to define rapidly the genetic changes responsible. Changes associated with artemisinin resistance are complex and seem to be evolving rapidly, especially in Southeast Asia. This is a rare chance to observe the early stages in evolution of resistance, and to develop strategies to reverse or mitigate the trend and to protect these key medicines.