Resistance to many antimalaria drugs developed on the Cambodia-Thailand border long before developing elsewhere. Because antimalaria resistance is now a global problem, artemisinin-based combination therapies (ACTs) are the first-line therapies in most malaria-endemic countries. However, recent clinical and molecular studies suggest the emergence of ACT-resistant Plasmodium falciparum infections in the Cambodia-Thailand border area, where standard ACT is artesunate and mefloquine. These ACT failures might be caused by high-level mefloquine resistance because mefloquine was used for monotherapy long before the introduction of ACT. This observation raises 2 questions. First, how can existing P. falciparum-resistant strains be controlled? Second, how can the evolution of new ACT- resistant strains be avoided elsewhere, e.g., in Africa? Enforcement of rational drug use and improved diagnostic capacity are among the measures needed to avoid and contain ACT resistance.