Cancer is a critical global health-care problem with limited therapeutic options. Since cancers are life-threatening illnesses, the identification of a promising oncotarget and its clinical correlates are relevant. Mounting evidence has emerged indicating that REG gamma (REGγ), a member of the 11S proteasome activators, plays a pivotal role in the development of multiple human cancers. However, an elaborate summary on the association between REGγ and cancer is still lacking. In this Review, we discuss how REGγ, through its ATP- and ubiquitin-independent manners, represents a promising cancer biomarker and therapeutic oncotarget for multiple human cancers. Aberrant REGγ expression closely associated with tumorigenesis attributes to its biological functions for controlling and regulating cell cycle, proliferation, migration, invasion, angiogenesis, and metastasis of the cancer cells by degrading proteins of cytosol and nucleus in the eukaryotic cells. REGγ serves as a molecular switch to activate multifarious oncogenic signaling pathways, such as MAPK/p38, TGF-β/Smad, and Wnt/β-catenin. The review describes that targeting REGγ may provide new diagnostic and therapeutic applications in cancer.