The region around the Mekong River delta is infamous for its malaria parasites. Twice already—in the 1950s and the 1960s—they have developed resistance to key drugs, and the underlying mutations spread inexorably around the world, forcing public health officials to find new ways to fight the disease. Now it is happening again. Over the last decade, artemisinin, the most powerful drug available to cure malaria, has failed in more and more people in Cambodia, Myanmar, Vietnam, Laos, and border regions of Thailand. Researchers and public health experts worry that history will repeat itself and the resistant parasites will go global. Though efforts to contain and eliminate resistant strains have been so far unsuccessful, two papers published online this week in Science offer new insights into the genes behind the threat—insights that should help scientists identify and track resistant parasites and perhaps find better ways to kill them.