The chromosomal translocation t(11:14) is associated with human lymphoid neoplasia affecting centrocytic B‐cells of intermediate differentiation. As a consequence the cyclin D1 (bcl‐1) gene is juxtaposed to the immunoglobulin heavy chain enhancer E mu. To show that transcriptional activation of cyclin D1 is causally involved in the generation of B‐cell neoplasia we have generated transgenic mice that carry a cyclin D1 gene under the transcriptional control of the E mu element. E mu cyclin D1 transgenic mice show only very subtle alterations in the cycling behaviour of B‐cell populations in the bone marrow compared with normal mice and do not develop lymphoid tumours. However, E mu‐directed coexpression of cyclin D1 and N‐MYC or L‐MYC in double transgenic mice reveals a strong cooperative effect between MYC and cyclin D1 provoking the rapid development of clonal pre‐B and B‐cell lymphomas. Interestingly, crossing of cyclin D1 transgenic mice with E mu L‐myc transgenics that express their transgene in both B‐ and T‐cells but predominantly develop T‐cell tumours leads in double transgenics exclusively to B‐cell neoplasia. The data presented here demonstrate that transcriptional activation of cyclin D1 can oncogenically transform B‐cells in concert with a myc gene. They establish cyclin D1 as a proto‐oncogene whose activity appears to depend on a specific cell type as well as on a specific cooperating partner and link disturbances in the regulation of cell cycle progression to the development of human malignancies.