The two paracrine melanogenic cytokines, stem cell factor (SCF) and endothelin-1 (ET-1), have been demonstrated to play pivotal roles in skin pigmentation including UVB-induced pigmentation and senile lentigo. However, little is known regarding their interactive effect on skin pigmentation. In order to investigate their roles in vivo, facultative pigmentation of human skin xenografts on severe combined immunodeficient (SCID) mice was assessed. After 1 week of acclimation in a pathogen-free barrier, dermatomed fresh cadaveric skin was surgically grafted onto the back of the mice and allowed to heal for 5-6 weeks prior to cytokine administration. Intradermal injections of SCF at 0.7 or 2.0 microg significantly increased skin pigmentation when compared to vehicle control. Despite the lack of a dose-dependent pigmentation response following ET-1 administration, the combination of 0.2 microg SCF and 0.1 microg ET-1 demonstrated a statistically significant increase in tyrosinase gene expression substantiated by the enhancement of melanin content and skin pigmentation compared to treatment with SCF alone or ET-1 alone. These findings establish an in vivo interaction between SCF and ET-1 with regard to their capacity to effect an increase in skin pigmentation.