Melanoma is the most aggressive form of skin cancer and results from transformed melanocytes. Melanomagenesis is influenced by both genetic and environmental factors. Exposure to Ultra Violet Radiation (UVR) is accepted as one of the most common environmental factors leading to melanomagenesis. The Nucleotide Excision Repair (NER) pathway is very significant during UVR exposure because it is responsible for repairing UVR-induced DNA damage. Xeroderma Pigmentosum (XP) is an autosomal recessive disorder resulting from deficiencies in any of the eight XP complementation group genes, which code for many proteins indispensable to the NER pathway. XP patients exhibit extreme sensitivity to UVR and a high predisposition to developing skin cancers, including melanoma. Upon being exposed to UVR, Xpatm1Tnka-deficient mice, which share many characteristics of XP patients, develop skin cancers, but not melanoma. The endothelin 3 (Edn3) pathway is critical for the development, proliferation, survival and migration of melanocyte precursor cells. The aim of this study was to develop a novel transgenic UVR-induced melanoma mouse model deficient in XPA in conjunction with overexpression of the EDN3 pathway. Three groups of transgenic mice that overexpress the EDN3 pathway under control of the keratin 5 promoter Tg(KRT5-rtTA)1Glk Tg(tetO-Edn3,-lacZ)Kosl (aka K5-Edn3) and have Xpatm1Tnka heterozygous or homozygous mutations (Xpa-/- K5-Edn3, Xpa+/- K5-Edn3 and Xpa+/+ K5-Edn3) were either exposed to a single suberythemal neonatal dose of UVR at 3.5 days, two doses of UVR (at 3.5 days and 6 weeks), or a single dose of UVR at 6 weeks during adulthood. Only transgenic K5-Edn3 mice developed melanomas, and animals exposed to one dose of UVR at 6 weeks of age did not develop any melanomas. Xpa-/- K5-Edn3 mice showed increased penetrance (60%, n=10) and earlier disease appearance, when compared to Xpa+/- K5-Edn3 (46%, n=13) and Xpa+/+ K5-Edn3 (19%, n=16). These results suggest that neonatal UVR exposure along with the over-activation of the EDN3 pathway is sufficient for melanomagenesis in mice, and is enhanced by deficiencies in the NER pathway.