Summary:Because of the binding of chloroquine to various tissue components and the lysosomotropism of chloroquine, its pharmacokinetics exhibit large apparent volumes of distribution, partial recoveries in urine, and persistence of low blood levels. These complexities have been reinvestigated with modern, highly sensitive methods for the determination of the drug and its major metabolite, desethylchloroquine, which reaches blood levels of about one‐third those of the parent drug and constitutes about one‐fifith of the 56% of drug accounted for by urinary recovery. Bioavailability is essentially complete, apparent volumes of distribution range up to 800 L/kg, and the pharmacokinetic data are generally accomodated by three compartment models. Half‐lives for the terminal component are 1 to 2 months, but the terminal phases may be of minor importance in effectiveness. Dose dependence, i.e. nonlinearity in the relationship of dose and area under the plasma curve, apparently is not a factor. Some of the most recent studies, designed to provide a rationale for safer parenteral administration, have made possible computer‐generated optimal infusion regimens. Revised schedules of loading and maintenance oral doses for antimalarial therapy have resulted from other pharmacokinetic studies. The in vitro antimalarial potencies of the two optical enantiomers of chloroquine are identical, but recent data suggest stereospecific differences in metabolic rates and renal secretion mechanisms. The marked uptake of chloroquine into the acidic food vacuoles of parasites resident in erythrocytes is assumed to underlie its antimalarial action, but mechanisms other than the previously assumed alkalization of the vacuole, possibly inhibition of phospholipid metabolism, now seem more likely to inhibit parasite function. Mild immunosuppression with inhibition of the elaboration of rheumatoid factor and acute phase reactants is a likely mechanism for the beneficial effects of chloroquine in rheumatoid arthritis. Blockade of interleukin‐1 release could lead to these effects and is one of the few instances in which the low chloroquine levels attainable in human serum can be shown to affect immunological reactions.