The pre-B lymphoma in the inbred mouse strain SL/Kh is an excellent multifactorial disease model. The endogenous murine leukemia virus provirus Emv11, genetically acquired from an AKR progenitor, is the pathogenetic agent that reintegrates to dysregulate several host genes, i.e., Stat5a, Evi3, c-Myc, N-Myc, Stat5b, and others. Constitutive activation of Stat5a either by provirus integration or by transfection of the active mutant Stat5a cDNA transforms pre-B cells in bone marrow. Genetically determined expansion of early B cells and a dominant SL/Kh MHC allele predispose the animals to succumb to pre-B lymphomas. A number of other host genetic and epigenetic factors that determine the types of lymphomas, susceptibility to lymphomas, and length of the latent period are discussed.