Adult T cell Leukemia (ATL) is an aggressive lymphoproliferative malignancy secondary to infection by the human T-cell leukemia virus type I (HTLV-I) and is associated with a dismal prognosis. ATL leukemogenesis remains enigmatic. In the era of precision medicine in oncology, mouse models offer one of the most efficient in vivo tools for the understanding of the disease biology and developing novel targeted therapies. This review provides an up-to-date and comprehensive account of mouse models developed in the context of ATL and HTLV-I infection. Murine ATL models include transgenic animals for the viral proteins Tax and HBZ, knock-outs for key cellular regulators, xenografts and humanized immune-deficient mice. The first two groups provide a key understanding of the role of viral and host genes in the development of ATL, as well as their relationship with the immunopathogenic processes. The third group represents a valuable platform to test new targeted therapies against ATL.