To directly examine a multistage carcinogenesis model and the role of UV light in human tissues, we grafted human skin onto mice with severe combined immunodeficiency disease. We found that the maximum dose of UV radiation in the B range (UVB; 280–320 nm) tolerated by these grafts was 500 J/m² three times weekly. One hundred fifty-one grafted mice were then randomized and observed for a median of 9 months in five groups: no treatment, chemical initiation alone, UVB as a complete carcinogen, initiation plus UVB promotion, and initiation plus UVB and phorbol ester promotion. Actinic damage and squamous atypia were found in grafts of all groups receiving UV treatment; unequivocal human squamous carcinomas developed in two of these. Species origin was verified by human-specific bisbenzimide staining and in situ hybridization for human-specific Alu segment. Overall basal proliferation, measured immunohistologically, was reduced in UV-treated grafts, but foci of hyperproliferation were seen in conjunction with the dedifferentiated expression of cytokeratins 1, 10 and 5, 8. Murine tumors also developed frequently, confirming the biological relevance of the carcinogenic strategies tested. These findings demonstrate that development of malignant human tumors can be experimentally accelerated in human tissue.