Although reports of antimalarial drug resistance emerged as early as 1910 from South America, the first event that really had a major impact on malaria control and drug development was the emergence of chloroquine resistance in the 2nd half of the 20th century. The appearance of resistance to chloroquine has marked the onset of a race between the development of ever new generations of antimalarial drugs and the emergence of resistance to these antimalarials, finally culminating in the emergence of clinical artemisinin resistance which was first reported in 2008. The potentially devastating impact of resistance to a drug that has been adopted as the first line drug for the treatment of uncomplicated falciparum malaria by virtually all malaria control programs throughout the malaria-endemic world, and for which there currently is no successor in sight should it truly fall victim to widespread drug resistance, calls for strategies to extend the useful life spans of currently available antimalarial drugs while at the same time stepping up efforts to develop novel combination therapies not based on artemisinins.