It is well known that amphibian Kupffer cells (KCs) contain eumelanins. In this paper, we demonstrate through a molecular analysis that Rana esculenta KCs synthesize high levels of mRNA for tyrosinase and through cytochemistry that they possess dopa oxidase activity: both these data prove that frog KCs are capable of autonomously synthesizing eumelanins. On the other hand, by using a highly sensitive reverse transcription-polymerase chain reaction assay we clearly show that in mammalian KCs the tyrosinase gene is not expressed. Quite unexpectedly, we have detected tyrosinase mRNA in Rana esculenta spleen, lung, and heart; to explain this finding, we suggest that it could be due to the presence of pigmented macrophages within the spleen, that probably behave as KCs, and of melanophores in lung and heart. It also may be hypothesized that the Rana esculenta tyrosinase gene, as opposed to its mammalian counterpart, is expressed in many cell types because its promoter contains sequences that are recognized by widely synthesized transcription factors. Our experiments also demonstrate that there is an inverse correlation between the amount of tyrosinase mRNA and melanin content, and that populations of terminally differentiated KCs are characterized by a high degree of apoptosis. Based on these data, we propose that differentiating KCs start accumulating eumelanins, as a result of previous expression of high levels of tyrosinase and of dopa oxidase activity, acquire the full KC phenotype (characterized by both phagocytic and melanosynthetic ability), and then undergo apoptosis. Accordingly, we propose that these cells could represent an interesting model to study, at the molecular level, the relationship between differentiation, specific gene expression, and programmed cell death in higher eukaryotes.