HTLV-1 and HTLV-2 are highly related complex retroviruses that have been studied intensely for nearly three decades because of their association with neoplasia, neuropathology, and/or their capacity to transform primary human T lymphocytes. The study of HTLV also represents an attractive model that has allowed investigators to dissect the mechanism of various cellular processes, several of which may be critical steps in HTLV-mediated pathogenesis. Both HTLV-1 and HTLV-2 can efficiently immortalize and transform T lymphocytes in cell culture and persist in infected individuals or experimental animals. However, the clinical manifestations of these two viruses differ significantly. HTLV-1 is associated with adult T-cell leukemia (ATL) and a variety of immune-mediated disorders including the chronic neurological disease termed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). In contrast, HTLV-2 is much less pathogenic with reports of only a few cases of variant hairy cell leukemia and neurological disease associated with infection. The limited number of individuals shown to harbor HTLV-2 in association with specific diseases has, to date, precluded convincing epidemiological demonstration of a definitive etiologic role of HTLV-2 in human disease. Therefore, it has become clear that comparative studies designed to elucidate the mechanisms by which HTLV-1 and HTLV-2 determine distinct outcomes are likely to provide fundamental insights into the initiation of multistep leukemogenesis.