The tumor suppressor p14/p19ARF regulates Mdm2, which is known for controlling the p53 tumor suppressor. Here we report that loss of one allele of Mdm2 in cells that lack ARF resulted in a decreased rate of proliferation, fewer chromosomal aberrations, and suppression of Ras-induced transformation. Moreover, a haploinsufficiency of Mdm2 inhibited spontaneous tumor development in ARF-null mice. Remarkably, Mdm2+/-ARF-/- mice survived an average of 6 months longer than Mdm2+/+ARF-/- mice. The spectrum of tumors that arose in Mdm2+/-ARF-/- mice did not significantly differ from those that developed in mice lacking only ARF. However, the extended tumor latency allowed for the emergence of multiple primary tumors in a third of the Mdm2+/-ARF-/- mice, as compared to the single tumor type that arose in ARF-null only mice. Therefore, a decrease in Mdm2 levels restored regulation of critical cellular processes that are altered during transformation and that occur in the absence of ARF. Our findings also indicate that Mdm2 can function independently from ARF and imply that targeting Mdm2 in tumors that lack ARF expression should be an effective therapeutic approach.