The proteasome is the final player in the regulated degradation of intracellularproteins through in both ubiquitin-dependent and ubiquitin-independent proteolyticpathways. In eukaryotic cells, the ubiquitin-proteasome system coordinates thepolyubiquitination and subsequent proteolysis of unwanted proteins, crucial to normalcellular homeostasis. The first-in-class proteasome inhibitor, bortezomib. promotesapoptosis and chemosensitization of cancer cells, and is used clinically as either a singleagentchemotherapeutic or in combination with other drugs. Natural products offermedicinal chemists with a cornucopia of diverse chemical scaffolds and bioactivesubstructures, and historically have represented an important source of new drugs.Salinosporamide A (NPI-0052), a second-generation proteasome inhibitor of marinemicrobial origin, has been effective against bortezomib-resistant cancers and has enteredPhase I clinical trials. This review discusses the application of natural products asinhibitors of the ubiquitin-proteasome system through targeting of both conventional proteolytic pathways as well as those involving ubiquitin-like proteins, such as NEDD8,which have recently emerged as novel anti-cancer targets. © 2012 by Nova Science Publishers, Inc. All rights reserved.