Human T-cell leukemia virus type I (HTLV-1) was the first human pathogenic retrovirus to be discovered. HTLV-1 induces a T-cell malignancy, adult T-cell leukemia-lymphoma (ATL), and inflammatory diseases, such as HTLV-1-associated myelopathy (HAM), HTLV-1 uveitis (HU), and HTLV-1-associated pulmonary disease (HAPD). Importantly, HTLV-1 maintains persistent infection by regulating viral gene expression and disrupting host signaling pathways — activities that are closely linked to its pathogenicity. By modulating the expression of viral genes, including tax and HTLV-1 bZIP factor (HBZ), HTLV-1 enables itself to evade host immune attack and to promote the clonal expansion of infected cells. In addition, HTLV-1 perturbs host signaling pathways, such as the transforming growth factor (TGF)-β signaling pathway, the IL-10/JAK/STAT signaling pathway, the nuclear factor-kappa B signaling pathway, the Wnt signaling pathway, and the Rb/E2F signaling pathway. Among these pathways, the first two have recently been demonstrated to be significant in the development of ATL. HBZ enhances the activation of the TGF-β signaling pathway and the production of an immunosuppressive cytokine, IL-10, activities which not only help the virus evade the host immune system but also contribute to the proliferation of HTLV-1–infected cells themselves. In addition, HBZ converts HTLV-1–infected cells into Treg-like cells, which further enhances their survival. Overall, HTLV-1 promotes the long-term survival of infected cells in vivo by regulating viral gene expression and disrupting host signaling pathways, thereby accelerating the development of HTLV-1-associated disease.