The feed-back auto-regulatory loop between p53 and MDM2 has been extensively investigated. MDM2 is under the transcriptional control of p53, and MDM2 acts as a negative regulator of p53. There is increasing evidence, however, supporting the notion that MDM2 has activities independent of p53. In the absence of p53, MDM2 may retain its role in cell cycle control, differentiation, cell fate determination, DNA repair, transcription regulation, signal transduction of steroid receptors, cellular response to hypoxia, internalization of surface receptors, and other processes. MDM2 also has oncogenic transformational activities independent of p53. Moreover, anti-MDM2 antisense oligonucleotides have in vitro and in vivo antitumor activity and chemosensitizing and radiosensitizing effects in several human cancer models, regardless of their p53 status. In this article, the p53 independent activities of MDM2 and its interactions with various cellular proteins are considered. The studies reviewed provide a basis for developing novel MDM2 inhibitors as a therapy against human malignancies.