The development of chloroquine as an antimalarial drug and the subsequent evolution of drug-resistant Plasmodium strains had major impacts on global public health in the 20th century. In P. falciparum, the cause of the most lethal human malaria, chloroquine resistance is linked to multiple mutations in PfCRT, a protein that likely functions as a transporter in the parasite's digestive vacuole membrane. Rapid diagnostic assays for PfCRT mutations are already employed as surveillance tools for drug resistance. Here, we review recent field studies that support the central role of PfCRT mutations in chloroquine resistance. These studies suggest chloroquine resistance arose in > or = 4 distinct geographic foci and substantiate an important role of immunity in the outcomes of resistant infections after chloroquine treatment. P. vivax, which also causes human malaria, appears to differ from P. falciparum in its mechanism of chloroquine resistance. Investigation of the resistance mechanisms and of the role of immunity in therapeutic outcomes will support new approaches to drugs that can take the place of chloroquine or augment its efficiency.