A T-to-G germline single nucleotide polymorphism in the promoter region of MDM2 (SNP309) has been reported to markedly accelerate tumor formation in humans suggesting that it may represent a powerful cancer predisposing allele. Since its first description in 2004, a large number of retrospective analyses involving a wide variety of human malignancies have been reported, showing conflicting results regarding the impact of Mdm2SNP309 status on cancer risk and response to cancer therapy. Here, we appraise the available information on the effect of Mdm2SNP309 in lymphoma and leukemia and discuss the factors that likely account for the conflicting results observed in the studies reported to date.