Resistance to quinoline antimalarials, especially to chloroquine and mefloquine has had a major impact on the treatment of malaria worldwide. In the period since 2000, significant progress has been made in understanding the origins of chloroquine resistance and to a lesser extent mefloquine resistance in Plasmodium falciparum. Chloroquine resistance correlates directly with mutations in the pfcrt gene of the parasite, while changes in another gene, pfmdr1, may also be related to chloroquine resistance in some strains. Mutations in pfcrt do not appear to correlate with mefloquine resistance, but some studies have implicated pfmdr1 in mefloquine resistance. Its involvement however, has not been definitively demonstrated. The protein products of these genes, PfCRT and Pgh-1 are both located in the food vacuole membrane of the parasite. Current evidence suggests that PfCRT is probably a transporter protein. Chloroquine appears to exit the food vacuole via this transporter in resistant PfCRT mutants. Pgh-1 on the other hand, resembles mammalian multi-drug resistance proteins and appears to be involved in expelling hydrophobic drugs from the food vacuole. Resistance reversing agents are believed to act by inhibiting these proteins. The currently known chloroquine- and mefloquine-resistance reversing agents are discussed in this review. This includes a discussion of structure-activity relationships in these compounds and hypotheses on their possible mechanisms of action. The status of current clinical applications is also briefly discussed.