Natural populations of Plasmodium falciparum without previous drug exposure are mixtures of individual parasites with different levels of response to a specific medicament. Exposure to sublethal drug concentrations will eliminate the highly and moderately sensitive individuals. The less sensitive part of the parasite population is being selected and given the opportunity of propagating. Underdosed mass drug administration and subcurative medication have this direct effect. An indirect effect with the same result is observed with drugs having a long half-life, where new infections invade the blood while subtherapeutic residual drug concentrations are still present. This militates against the use of drugs with long half-life in areas with intensive malaria transmission, and for a rational therapeutic use of alternative antimalarials based on reliable microscopic diagnosis, adequate dose regimens, post-treatment follow-up, further alternative treatment of recrudescences with the objective of radical cure.