Dietary administration of various chemically-unrelated hypolipidaemic (viz. hypotriglyceridaemic) drugs can induce liver carcinomas in rats or mice. These drugs, in common with other compounds exhibiting hypolipidaemic activity (e.g. di-(2-ethylhexyl) phthalate), produce in rodents an initial hepatic response characterized by the presence of (1) liver enlargement unaccompanied by frank histological liver damage, (2) proliferation of the smooth endoplasmic reticulum and (3) a striking increase in peroxisome numbers. Hypolipidaemic drugs exert differential effects on the activities of hepatic peroxisomal enzymes. Massive increases in the activities of enzymes involved in the β-oxidation of fatty acids and of carnitine acetyltransferase overshadow the modest increases, if any, in the activities of catalase and certain oxidase enzymes. It is suggested that the bioavailability of catalase in the liver peroxisomes of rodents treated with hypolipidaemic drugs is insufficient to cope with the detoxication of injurious H2O2 concentrations resulting from the considerably enhanced activity of H2O2-generating enzymes. Liver cells may thus be exposed to the cytotoxic or DNA-damaging potential of H2O2 as a result of the breakdown in homeostasis, and such exposure could lead to the subsequent development of neoplasia in the rodent liver. Evidence is accumulating that in man (as well as in monkeys) hypolipidaemic drugs do not elicit the peroxisome proliferative response that is associated with the disposal of hepatic lipids in rodents. Consequently it would not be justified to extrapolate the findings of rodent hepatocarcinogenesis to humans. Because of differences in response between the rodent liver and human liver towards the action of certain microsomal-enzyme inducers (phenobarbital, dieldrin, DDT, Ponceau MX and safrole), a similar conclusion has been reached—that the hepatocarcinogenicity of these compounds demonstrable in the rodent is not relevant to man. Moreover microsomal-enzyme inducers share remarkably close parallels with hypolipidaemic drugs in respect of the initial hepatic reaction, a lack of mutagenic potential/DNA interaction and the nature of the carcinogenic response. From the available data it is concluded that the hepatic peroxisome response is an important aetiological factor in liver cancer induced by hypolipidaemic drugs in rodents. The absence of a peroxisomal response in man (and subhuman primates) coupled with important differences in the way rats and humans handle lipoprotein remnants bound to liver cells strongly indicates that chronic administration of hypolipidaemic drugs is unlikely to present a liver-cancer risk in man.