The mechanism of action of the antifolate and quinoline antimalarials has been investigated over the last few decades, and recent advances should aid the development of new drugs to combat the increasingly refractile parasite. The molecular description of resistance to the antifolates has been well characterised and is due to structural changes in the target enzymes, but the factors involved in the parasite's ability to circumvent the action of the quinoline antimalarials have yet to be fully elucidated. This review discusses the mode of action of these drugs and the means used by the parasite to defeat our therapeutic ingenuity.