REGgamma, a member of the 11S proteasome activators, has been shown to bind and activate the 20S proteasome to promote proteasome-dependent degradation of important regulatory proteins, such as SRC-3 and cyclin-dependent kinase inhibitors p21, p16, and p19, in a ubiquitin- and ATP-independent manner. Furthermore, REGgamma has been shown to facilitate the turnover of tumor suppressor p53 by promoting MDM2-mediated p53 ubiquitination. The discovery that REGgamma regulates cell-cycle regulators is consistent with previous studies where REGgamma-deficient mice have shown retardation in body growth, decreased cell proliferation and increased apoptosis, indicating a potential role of REGgamma in cancer development. Additionally, REGgamma's ability to promote viral protein degradation suggests its involvement in viral pathogenesis. This review presents an overview of the function of REGgamma, a summary of the current literature, and insight into the possible biological function of REGgamma relating to cancer, viral pathogenesis, and other diseases.