Viruses confiscate cellular components of the ubiquitin-proteasome system (UPS) to facilitate many aspects of the infectious cycle. The 26S proteasome is an ATP-dependent, multisubunit proteolytic machine present in all eukaryotic cells. The proteasome executes the controlled degradation of functional proteins, as well as the hydrolysis of aberrantly folded polypeptides. There is growing evidence for the role of the UPS in viral entry. The UPS assists in several steps of the initiation of infection, including endosomal escape of the entering virion, intracellular transport of incoming nucleocapsids and uncoating of the viral genome. Inhibitors of proteasome activity, including MG132, epoxomicin, lactacystin and bortezomib have been integral to developments in this area. Here, we review the mechanistic details of UPS involvement in the entry process of viruses from a multitude of families. The possibility of proteasome inhibitors as therapeutic antiviral agents is highlighted.