Congenitally immunodeficient strains of mice have proven valuable in the development of relevant models to study human tumor biology, metastases, and immunotherapy. Local invasion and extensive multiorgan metastases in athymic mice have been obtained following orthotopic implantation or onplantation of histologically intact fragments of human tumors. In C.B-17 severe combined immunodeficient (SCID) mice or in triple immunodeficient, beige/nude/xid (BNX) mice, the development and spread of inoculated human leukemia/lymphoma and/or melanoma have mimicked, in some cases, those observed in patients. Reports of reconstitution of SCID and BNX mice with human myeloid or lymphoid cells have suggested that these models might be useful for the study of human immune responses to autologous tumors in vivo. The severe immunocompromised status of these mice have also led to evaluations of the therapeutic efficacy of adoptively transferred, tumor-reactive human T cells. In this report, we review the pertinent information currently available on the use of congenitally immunodeficient mice in studies of human cancer biology and treatment.