Dehydroepiandrosterone (DHEA), the main adrenal steroid in humans and a precursor in androgen and estrogen biosynthesis, acts as a hepatocarcinogen in the rat when given at high doses. The tumour incidence is higher in females than in males. The metabolism of DHEA is different in females and males, and it is not known whether DHEA or its metabolites are the carcinogenic agents. Furthermore, DHEA causes a strong oxidative damage of mitochondrial and microsomal membranes. DHEA-administration results in proliferation of peroxisomes which occur predominantly in the perivenular area of the liver lobule in females and shows a more random distribution in males. Induction of peroxisomal enzymes agrees with the lobular distribution of peroxisomes as shown by cytochemical methods. In addition to alterations in peroxisomal enzymes, a marked change in the activity and content of key enzyme of glucose and lipid metabolism is observed. Enzymes of glycolysis and gluconeogenesis are usually decreased while those of lipid metabolism are increased. Hepatocellular tumours develop from preneoplastic focal lesions characterized by an amphophilic phenotype, the latter being due to a strong proliferation of mitochondria which are closely associated with membranes of the rough endoplasmic reticulum. DHEA enhances hepatocarcinogenesis induced by other carcinogens such as nitrosamines when given in a two stage protocol. The glycogenotic/basophilic cell lineage of hepatocarcinogenesis typically induced by nitrosamines undergoes a modulation to the amphophilic phenotype under these conditions. Glycogenotic cell foci (GSF) and amphophilic cell foci (APF) express patterns of key enzymes of energy metabolism which are in many respects opposite. While GSF exhibit an enzyme pattern which mimics an insulin effect, the enzyme expression in APF resembles a thyromimetic effect. The enzyme pattern in GSF includes a reduction of gluconeogenic glucose-6-phosphatase and mitochondrial glycerol-3-phosphate dehydrogenase as compared to the surrounding tissue, while both enzymes are increased in APF. Intracellular signaling is also modulated by DHEA. Whereas the expression of IRS-1 is increased in GSF, it is unchanged in APF. The data strongly suggest that two different cellular lineages exist in hepatocarcinogenesis and that the glycogenotic/basophilic lineage is modulated into the amphophilic lineage by DHEA.