Multiple myeloma is an incurable malignancy, and there is currently no mouse model that fully recapitulates the development and progression of the disease. We now describe a transgenic mouse that expresses a Bcl-X_L transgene under the control of the 3′κ immunoglobulin light chain enhancer, which is most active in murine B cells in late developmental stages. These mice developed nonmalignant plasma cell foci in the bone marrow and soft tissues and hyaline tubular casts in the kidneys. Median survival of the 3′KE/Bcl-X_L mice was similar to littermate controls. When the 3′KE/Bcl-X_L mouse was crossed to an Eμ/c-Myc transgenic mouse, median survival of double transgenic progeny was 5.5 weeks. Peripheral blood and soft tissues were infiltrated with immature/mature B cells, and plasma cell lesions were identified in the bone marrow of all mice coexpressing Bcl-X_L and c-Myc. These B- and plasma cell lesions demonstrated features consistent with malignancy. These results indicate that the 3′κ immunoglobulin light chain enhancer can effectively target expression of Bcl-X_L to B cells in late developmental stages, and they provide direct evidence that Bcl-X_L can contribute to plasmacytomagenesis. Furthermore, this murine model serves as an important step in developing a novel genetically induced mouse model of plasma cell malignancies exhibiting bone marrow involvement. (Blood. 2004;103:2779-2786)