Mdm2 harnesses the p53 tumor suppressor, yet loss of one Mdm2 allele in Mdm2+/− mice has heretofore not been shown to impair tumor development. Here we report that Mdm2 haplo‐insufficiency profoundly suppresses lymphomagenesis in Eμ‐myc transgenic mice. Mdm2+/− Eμ‐myc transgenics had greatly protracted rates of B cell lymphoma development with life spans twice that of wild‐type transgenic littermates. Im paired lymphoma development was associated with drastic reductions in peripheral B cell numbers in Mdm2+/− Eμ‐myc transgenics, and primary pre‐B cells from Mdm2+/− Eμ‐myc transgenics and Mdm2+/− littermates were extremely susceptible to spontaneous apoptosis. Loss of p53 rescued all of the effects of Mdm2 haplo‐insufficiency, indicating they were p53 dependent. Furthermore, half of the lymphomas that ultimately emerged in Mdm2+/− Eμ‐myc transgenics harbored inactivating mutations in p53, and the majority overcame haplo‐insufficiency by overexpressing Mdm2. These results support the concept that Mdm2 functions are rate limiting in lymphomagenesis and that targeting Mdm2 will enhance p53‐mediated apoptosis, compromising tumor development and/or maintenance.