Publisher Summary This chapter discusses the immunological aspects of retrovirus oncogenesis, with particular emphasis on the mouse system and specific immune unresponsiveness. Members of the retrovirus family have been causally associated with the tumor induction in host animals. Several hypotheses have been advanced to explain the ways oncogene-devoid retroviruses manage to subvert the proliferative machinery of cells. In the experimental systems, murine leukemia virus (MuLV) expression on lymphoreticular cells during the perinatal period must be considered as the initial step of multiple events eventually leading to lymphoma development. Endogenous M-MuLV activation during embryogenesis in Mov-13 mice or in the few days following birth in BALB/Mo mice, as well as exogenous M-MuLV infection and expression in newborn mice, render the still immature immune system tolerant to viral antigens, thus, enabling the establishment of a lifelong virus carrier state. However, it is commonly held that the MuLV system is a misleading model for the studies of retrovirus-induced human diseases and that better human analogs are the feline and bovine leukemia virus systems.