Mdm2 has been well characterized as a negative regulator of the tumor suppressor p53. Recent studies have shown that Mdm2 is activated in response to a variety of oncogenic pathways independent of p53. Although its role as an oncogene via suppression of p53 function remains clear, growing evidence argues for p53-independent effects, as well as the remarkable possibility that Mdm2 has tumor suppressor functions in the appropriate context. Hence, Mdm2 is proving to be a key player in human cancer in its own right, and thus an important target for therapeutic intervention.