D eregulated expression of both Myc and Bcl-X_L are consistent features of human plasma cell neoplasms (PCNs). To investigate whether targeted expression of Myc and Bcl-X_L in mouse plasma cells might lead to an improved model of human PCN, we generated Myc transgenics by inserting a single-copy histidine-tagged mouse Myc gene, Myc^His, into the mouse Ig heavy-chain Cα locus. We also generated Bcl-X_L transgenic mice that contain a multicopy Flag-tagged mouse Bcl-x^Flag transgene driven by the mouse Ig κ light-chain 3′ enhancer. Single-transgenic Bcl-X_L mice remained tumor free by 380 days of age, whereas single-transgenic Myc mice developed B cell tumors infrequently (4 of 43, 9.3%). In contrast, double-transgenic Myc/Bcl-X_L mice developed plasma cell tumors with short onset (135 days on average) and full penetrance (100% tumor incidence). These tumors produced monoclonal Ig, infiltrated the bone marrow, and contained elevated amounts of Myc^His and Bcl-X_L^Flag proteins compared with the plasma cells that accumulated in large numbers in young tumor-free Myc/Bcl-X_L mice. Our findings demonstrate that the enforced expression of Myc and Bcl-X_L by Ig enhancers with peak activity in plasma cells generates a mouse model of human PCN that recapitulates some features of human multiple myeloma.