In human skin, most studies have suggested a role of c-fos or c-fos related genes in keratinocyte differentiation. The aim of our work was to more directly address this question by transfecting more or less differentiated keratinocyte cell lines (A431 and HaCaT) with constitutive expression vectors for c-Fos or c-Fos + c-Jun. Our results showed that c-Fos expression decreased keratinocyte growth, yet addition of c-Jun seemed to revert this c-Fos induced growth inhibition. Whereas no obvious differentiation program was turned on by c-Fos or c-Fos + c-Jun expression in our tissular model, apoptotic figures were observed and confirmed by in situ DNA fragmentation studies. These results do not rule out a role of c-Fos in keratinocyte differentiation but may indicate that the cell lines we used have reached an irreversible state of transformation so that they no longer respond to differentiation signals and rather die from apoptosis. These data add further evidence in favor of a role of c-Fos in epidermal homeostasis.