Targeting the ubiquitin-proteasome pathway gained more attention as a rational approach in the treatment of human cancer. The 26S proteasome (2000-kDa) complex, which degrades ubiquitinated proteins, contains in addition to the 20S proteasome a 19S regulatory complex composed of multiple ATP ases and components necessary for binding protein substrates. Accordingly, proteasome is considered an exciting target for the development of anticancer therapies. Inhibition of proteasome machinery has shown a positive clinical benefit for cancer patients. Thus, the highlight of the mechanistic role of proteasome regulators, both inhibitors and activators, may help to improve the outcome of tumor treatment. In this review, we will focus on the molecular action of proteasome regulators in tumor treatment.