For 40 years scientists have hotly debated the questions of how chloroquine kills malarial parasites and how resistance to this once first-line antimalarial drug has evolved. While an end to these debates is not in sight, as a result of the complexity of the subject, new findings have come forward that give the discussion a new direction. In this paper we will summarize current knowledge on chloroquine's antimalarial mode of action and the genesis of the resistant phenotype in the human malarial parasite Plasmodium falciparum, with special emphasis on the most recent developments in this field.