Quinoline-containing antimalarials are cationic amphiphiles which accumulate to high levels in lysosomes and are known to interact with membrane phospholipids. It was therefore hypothesized that they could exert their antimalarial effect by compromising the integrity of the parasite's acidic organelles. To test this hypothesis, the effects of chloroquine (CQ), quinine (Q) and mefloquine (MQ) on the osmotic stability of human red blood cells exposed to hypotonic solutions have been investigated. With CQ and Q stabilization was observed at pH 7.8 and destabilization at pH 5, indicating that destabilization is caused by the protonated forms of the drugs. With MQ the pH dependence was reversed, i.e. it destabilized at pH 7.8 and stabilized at pH 5, suggesting that destabilization is caused by the unprotonated drug. MQ caused cell lysis at the tenth millimolar range by a detergent effect. The possible destabilizing effect of drugs on the membranes of Plasmodium falciparum acidic organelles was investigated in metabolically-labelled parasites. We expected an increase in degradation of parasite proteins if drugs did indeed cause the release of acid hydrolases from destabilized organelles to the cytoplasm. No effect of drugs on parasite protein degradation could be observed, but protein synthesis was inhibited at therapeutic drug concentrations. These results imply that quinoline-containing antimalarials do not compromise the integrity of parasite acidic organelles, and that inhibition of protein synthesis results from a limited supply of essential amino acid(s) due to the demonstrable drug-mediated suppression of parasite digestion of host cell cytosol.