The ubiquitin proteasome system has been validated as a target of cancer therapies evident by the US FDA approval of anticancer 20S proteasome inhibitors. Deubiquitinating enzymes (DUBs), an essential component of the ubiquitin proteasome system, regulate cellular processes through the removal of ubiquitin from ubiquitinated-tagged proteins. The deubiquitination process has been linked with cancer and other pathologies. As such, the study of proteasomal DUBs and their inhibitors has garnered interest as a novel strategy to improve current cancer therapies, especially for cancers resistant to 20S proteasome inhibitors. This article reviews proteasomal DUB inhibitors in the context of: discovery through rational design approach, discovery from searching natural products and discovery from repurposing old drugs, and offers a future perspective.