Inflammation plays a central role in the pathogenesis of atherosclerosis and restenosis following intra-arterial intervention. The ubiquitin-proteasome pathway is crucial for the control of biological processes involving inflammation, cell proliferation and apoptosis that contribute to atherogenesis and neointima formation. Accordingly, it is reasonable to postulate that inhibition of the proteasome could have a major role in prevention and treatment of atherosclerosis and restenosis. In eukaryotes, the ubiquitin-proteasome system is responsible for degradation of most intracellular proteins. Among the diverse substrates of the system are the cell cycle regulators (cyclin A, B, D, and E), mediators of apoptosis (p53, c-myc, and bcl2) and IkB, the major inhibitory protein of nuclear factor (NF)-κB. Natural and synthetic proteasomal inhibitors have been developed and evaluated in preclinical studies of reperfusion and vascular injury. Additionally, a metabolic pathway, reversible modification of the proteasome by addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to Ser and Thr residues (O-glycosylation), has been shown to decrease proteasomal function, is inducible by various forms of stress and may be protective in the cardiovascular system. This article reviews the current data available on the ubiquitinproteasome system, its inhibition by specific pharmaceutical inhibitors and by O-glycosylation, and their possible therapeutic implications in the prevention of cardiovascular disease.