Ubiquitin-proteasome system is emerging as an immensely important enzymatic pathway playing central roles in protein degradation and signaling in numerous human diseases. Building on the prolific success of targeting the ubiquitin-proteasome system in cancer, the broader scientific community is currently seeking to elucidate the potential roles of this enzymatic system in other diseases such as autoimmune and neurodegenerative. A number of promising protein targets for these disorders have been identified in the recent years, and this review briefly summarizes the most recent advances in the field. © 2016, Springer Science+Business Media New York.