Human T cell leukemia virus type I (HTLV-I) is the agent of a wide spectrum of human diseases. The mechanisms by which a single virus can cause neurodegenerative disorders as well as leukemia is still a matter of debate. Transgenic mice have been used to assess the contribution of different viral elements in viral tropism as well as on cell transformation in vivo. In particular, transgenic models were generated to study the tissue specificity of expression directed by the viral long terminal repeat and the pathological effects induced by the Tax protein of HTLV-I. These models have led to a description of the cell types able to support the viral expression in vivo, and the use of Tax-transgenic mice has demonstrated that this protein is oncogenic and able to induce muscular atrophy and arthropathies. Finally, these models could provide a useful system to study therapeutic approaches for HTLV-I-associated diseases.