The ubiquitin-proteasome system (UPS) is one of the two major proteolytic systems in cells, which degrades most cellular, nuclear and myofibrillar proteins. A main function of the UPS is to prevent accumulation of damaged, misfolded and mutant proteins. Our work showed that cardiac myosin-binding protein C (cMyBP-C) mutants resulting from gene mutations causing hypertrophic cardiomyopathy (HCM) are degraded by the UPS via the E3 ubiquitin ligase atrogin-1 after gene transfer in cardiac myocytes. This was associated with impairment of the function of the proteasome. Furthermore, we showed that the UPS and the nonsense-mediated mRNA decay regulate the levels of cMyBP-C mutants in homozygous cMyBP-C knock-in mice with HCM (cMyBP-C-KI). Interestingly, higher steady-state levels of ubiquitinated proteins and higher chymotrypsin-like activity of the proteasome were observed in cMyBP-C-KI mice, suggesting UPS alterations. The alterations of the UPS have been found in human heart failure and in several experimental models of pathological or physiological left ventricular hypertrophy, and/or cardiac dysfunction. Recent data showed that inhibition of the proteasome with different inhibitors in cells or in mice prevents the development of hypertrophy or reduced the severity of the existing hypertrophy. The author will give an overview on the UPS in cardiac dysfunction and hypertrophic cardiomyopathy with a specific focus on cMyBP-C.