The malaria parasite has been allowed to get perilously close to winning the upper hand in the race between new drugs and resistance development. Today, just one class of drugs is left to avoid a public health disaster of global proportions, the artemisinins, and even they are showing signs of a possible impending failure. Rational approaches to overcoming antimalarial drug resistance are difficult for several reasons. Resistance mechanisms are varied and imperfectly known across Plasmodium species and often there is not a good correlation between in vitro drug susceptibility, molecular markers of resistance and therapeutic failure, except for antimalarials acting on well defined molecular targets such as atovaquone and the antifolates. Drugs with more complex modes of action are expected to have correspondingly complex resistance mechanisms. Molecular markers of resistance for the most widely used quinoline, chloroquine, have been identified, but they are not applicable to all parasite species and perhaps not even to all strains. Analyses of drug resistance in vitro are also limited by the fact that only one malaria parasite species, Plasmodium falciparum, is amenable to long term culture. Nevertheless, reducing the risk of premature therapeutic failure due to quick resistance emergence needs to be considered from the earliest stages of drug discovery. In the present review we attempt to summarize the main mechanisms of resistance to current antimalarials and provide information on already available assays to estimate the propensity of a new molecule to select for resistant parasites.