The speed and stage specificity of antimalarial drug action on the metabolic activities of cultured Plasmodium falciparum were studied for chloroquine (CQ), quinine (QN), artemisinin (AR), and sodium artelinate (SA). CQ had the most rapid onset of action on [3H]hypoxanthine and [3H]isoleucine uptake, reaching 50% of its maximum effect in 1.8 hr compared with 3.5-7.4 hr for the other three drugs. In contrast there was a lag time of 1-4 hr before AR and SA had a measurable inhibitory effect, although after this delay antimalarial action was very rapid. Parasite glycolysis was relatively drug resistant; the inhibition of lactate production was < 60% of that for [3H]hypoxanthine and [3H]isoleucine uptake. The susceptibility of P. falciparum changed markedly as the parasite matured. Maximum drug effects occurred at the late ring and early trophozoite stage, which corresponds to the time at which the most rapid increases in synthetic and glycolytic activities occur. Mature schizonts and young rings were relatively unaffected by the antimalarial drugs. Young rings were particularly resistant to QN. Schizonts multiplied successfully in the presence of relatively high concentrations of all four drugs. The two artemisinin compounds had the broadest time window of action and may be particularly suitable for the treatment of severe malaria.