Human T-cell leukemia virus type 1 (HTLV-1) was discovered in 1980 as the first, and to date, the only retrovirus that causes human cancer. While HTLV-1 infection is generally asymptomatic, 3-5% of infected individuals develop a T cell neoplasm known as adult T cell leukemia/lymphoma (ATL) decades after infection. Since its discovery, HTLV-1 has served as a model for understanding retroviral oncogenesis, transcriptional regulation, cellular signal transduction, and cell-associated viral infection and spread. Much of the initial research was focused on the viral trans-activator/oncoprotein, Tax. Over the past decade, the study of HTLV-1 has entered the genomic era. With the development of new systems for studying HTLV-1 infection and pathogenesis, the completion of the whole genome, exome and transcriptome sequencing analyses of ATL, and the discovery of HBZ as another HTLV-1 oncogene, many established concepts about how HTLV-1 infects, persists and causes disease have undergone substantial revision. This chapter seeks to integrate our current understanding of the mechanisms of action of Tax and HBZ with the comprehensive genomic information of ATL to provide an overview of how HTLV-1 infects, replicates and causes leukemia.