The review puts forward the concept of Direct Mutagen Risk Assessment through a discussion of the development of methods with which to measure immunologic and genetic responses to mutagens. Mutagenicity risk assessment, in this context, is the study of human somatic cell mutation occurring in vivo and is considered with attention to ideal criteria for detection of mutant cells. Immunotoxicity is addressed particularly in terms of the possible carcinogenic consequences of impaired cutaneous cell-mediated immunity. A section of this review reports the development and the exploitation of the Strauss-Albertini test for enumerating 6-thioquanine-resistant peripheral blood lymphocyte variants. Another section presents results from a system under development, designed to clone and quantitate mutant lymphocytes taken directly from the body. The Clonal Assay of Lymphocyte Mutagenesis (CALM) can confirm that variant cells are mutant and, potentially, could be used comparatively to measure genotoxicity in human or animal lymphocytes after in vivo or in vitro exposures to mutagens.