Viability-promoting genes such as BCL2 play an important role in human cancer but do not directly cause aggressive tumors. BCL2 transgenic mice develop lymphoma at low frequency, hindering studies of tumorigenesis and its inhibition in the presence of such gene products. MCL1 is a member of the BCL2 family that is highly regulated endogenously and that promotes cell viability and immortalization when introduced exogenously. Mice expressing an MCL1 transgene in hematolymphoid tissues have now been monitored for an extended period and were found to develop lymphoma with long latency and at high probability (more than 85% over 2 years). In most cases, the disease was widely disseminated and of clonal B-cell origin. A variety of histologic subtypes were seen, prominently follicular lymphoma and diffuse large-cell lymphoma. MCL1 thus sets the stage for the development of lymphoma as does BCL2, disease occurring with high probability and recapitulating a spectrum of subtypes as seen in human patients. These findings with the transgene underscore the importance of the normal, highly regulated pattern of MCL1 expression, in addition to providing a model for studying tumorigenesis and its inhibition in the presence of a viability promoting BCL2 family member. (Blood. 2001;97:3902-3909)