The TCL1 mouse has been proposed as a mouse model for chronic lymphocytic leukemia. This review details how it resembles the aggressive form of the disease rather than the more common indolent form. Although fulfilled predictions in the human disease based on investigations in the mouse model are at present lacking, there are remarkable similarities between human and mouse leukemias that have led to interesting observations on the pathophysiology of chronic lymphocytic leukemia and have identified putative therapeutic targets.