Ubiquitination is a post-translational modification that plays a role in several cellular processes including cell cycle progression, cell proliferation, DNA replication and apoptosis. Ubiquitin-mediated signaling is frequently altered in cancer cells. Several tumor suppressors and oncogenes interact with enzymes of the ubiquitin-proteasome pathway that function in ubiquitin conjugation and deconjugation. Increasing evidence indicates that the ubiquitin-proteasome system (UPS) plays an important role in cancer development. Several small molecule inhibitors of the UPS have been applied to the treatment of cancer. The current review focuses on the role of the UPS in cancer development and the development of UPS inhibitors for cancer treatment.