The Western Cambodia region 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 inevitably around the world, forcing public health sector to find new ways to contain the disease. It is now happening again. Over the years, artemisinin, the most powerful drug available for management of malaria, has reported in a substantial number of individuals in Cambodia, Myanmar, Vietnam, Laos, and border regions of Thailand. Researchers and public health experts worry that history may repeat itself and the resistant parasites spread globally. Recent discovery of drug resistance–associated genes, pfcrt, pfmdr1, dhfr, dhps, and k13 and applications of microsatellite markers flanking the genes have revealed of the evolution of resistant parasites to all classes of antimalarials and the geographical distribution of drug resistance. Here, we review our recent knowledge of the Origin and spread of parasite resistance to the previously used drugs (chloroquine, sulfadoxine/pyrimethamine) and artemisinin combination therapy. Though efforts to prevent and eliminate resistance so far are still unsuccessful, but, new advances into the genes other than the threat insight should help scientists identify and track resistant parasites including finding better ways to contain them