Several lines of evidence indicate that the liver is the predominant production site for EPO during the early stages of development. Moreover, in adults, it may contribute significantly to EPO production in some species. Independent of age hepatocytes are the major cellular sites of EPO gene expression in the liver, but quantitatively less significant expression also occurs in at least one additional type of nonparenchymal cell. Although some indirect evidence suggests that these nonparenchymal cells producing EPO may be Kupffer cells, their identity remains to be clarified. Regarding the mechanisms of the adaptation of hepatic EPO production to changes in oxygen availability in the organism, experiments with isolated perfused livers, mixed liver cell cultures, hepatoma cells, and, more recently, isolated hepatocytes have provided evidence that inherent cellular oxygen-sensing mechanisms exist and that external factors are not essential. The use of hepatoma cells has allowed investigation of these cellular mechanisms of oxygen-dependent gene control, and further studies in nontransformed hepatocytes may complement these studies.