The ubiquitin-proteasome pathway (UPP) is the major proteolytic process that degrades the intracellular proteins in a regulated way. Deregulation of the UPP has been implicated in the pathogenesis of a number of major human diseases including cancer, viral infections, neurodegenerative disorder, cardiovascular disorder, diabetes, etc. The successful market of a patented drug bortezomib validated the proteasome as an effective target in the treatment of cancers. It also demonstrated the potential of proteasome as a biological target in the design of the drugs against other major human diseases stated above. This review presents the development status of the proteasome inhibitors and their application in many diseases and recent patent coverage.