Since Hayflick’s pioneering work in the early sixties, human diploid fibroblasts have become a widely accepted in vitro model system for gerontological research. Most recently, Bayreuther and co-workers extended this experimental approach showing that fibroblasts in culture resemble in their design the hemopoietic stem-cell differentiation system. Using this model, we have found in human skin fibroblasts following mitomycin-C (MMC) treatment characteristic morphological changes of the fibroblasts and specific shifts in the [35S]methionine polypeptide pattern of the total cellular proteins which support the notion that MMC accelerates the differentiation pathway from mitotic (MF) to postmitotic fibroblasts (PMF). Ornithine decarboxylase (ODC) can be activated by ultraviolet light (UV) and is involved in the synthesis of polyamines which play a role in the regulation of DNA synthesis and cell proliferation. Therefore, ODC may participate in the modulation of gene expression. ODC may even serve as a biochemical marker of the mutagenic and carcinogenic effects of ultraviolet light; therefore, we tested this interesting enzyme in the fibroblast differentiation system. Indeed, we were able to show that UV-induced ODC response is significantly reduced in the MMC-induced postmitotic stage of fibroblasts originally derived from a 9-year-old female. We compared this finding with previous results from our laboratory, where we have demonstrated that ODC in human skin fibroblasts from younger donors can be significantly more stimulated by UV compared to the enzyme activities in fibroblasts from older donors. We conclude that UV-induced ODC response may serve as a marker of differentiation and aging. Our results also imply that the fibroblast differentiation system is a very useful tool to unravel the complex mechanisms of skin aging.