Adult T-cell leukemia/lymphoma (ATL) is an aggressive T cell neoplasm caused by infection with human T-cell leukemia virus type 1 (HTLV-1). Cells derived from ATL do not form tumors when injected in nude mice, a model commonly used in cancer research; this precludes the use of these animals for trials of new therapeutic agents for this disease. Instead, the first successful attempt to proliferate either leukemic cell lines from ATL patients or HTLV-1–transformed cells in vivo involved the use of severe combined immunodeficiency (SCID) mice that lack functional T and B cells; however, long latency periods are required for tumor formation in SCID mice, and well-characterized HTLV-1–transformed cell lines could not be engrafted in this model. Given that natural killer (NK) cell activity has been shown to play a key role in the rejection of these cells in SCID mice, SCID/beige (SCID/bg) and non-obese diabetic/SCID (NOD/SCID) mice, which have reduced NK cell activity, were used to overcome the poor infiltration rates of ATL–derived cells in vivo; however, this approach was only modestly successful. The recent development of novel immunodeficient mice, NOD/SCID/β2m^null and NOD/SCID/γc^null (NOG) mice, which display multiple immunological functional defects, prompted several researchers to inoculate these animals with HTLV-1 infected cell lines derived from both leukemic and in vitro–transformed cells. This approach resulted in the fast and reproducible appearance of progressively growing large tumors. These mice will therefore be widely used in the near future for the evaluation of new anticancer agents for ATL.