Considerable progress has been made in antimalarial research; however, much more effort is required to develop new antimalarials which overcome plasmodial resistance to clinically available drugs and limit the emergence of resistance. In particular, research must focus on understanding the mechanisms by which Plasmodium falciparum impedes the action of these drugs. In this review, we discuss the different in vitro and in vivo models used to adequately study resistance to antimalarial compounds. For each molecule studied, the best in vitro and/or in vivo model is highlighted with a detailed discussion of its validity in relation to field data on P. falciparum resistance.