Abstract: The ubiquitin-proteasome system (UPS), containing ubiquitin-activating enzyme (E1), ubuquitin-conjugating enzyme (E2s), ubiquitin-ligase (E3s) and 26S proteasome, is involved in the degradation of most intracellular proteins. One major function of UPS is to prevent accumulation of non-functional, potentially toxic proteins. Moreover, it has become clear that the UPS fulfills an important function in most aspects of eukaryotic biology, such as inflammation, cell proliferation, intracellular signaling, transcriptional control, and apoptosis. Recent studies demonstrated that the UPS regulates the initiation and progression of atherosclerosis, ischemia-reperfusion injury, familial cardiomyopathies, hypertrophic and heart failure. This review briefly summarizes present knowledge about structure, function, regulation of UPS and its pathophysiological role in cardiovascular diseases.