The cardiac proteasome is a complex, heterogeneous, and dynamic organelle. Its function is regulated by its molecular organization, post-translational modifications, and associated partner proteins. Pressure overload, ischaemic heart disease, or genetic mutations in contractile proteins can cause heart failure, during which misfolded protein levels are elevated. At the same time, numerous interconnected signal transduction pathways are activated that may modulate any of the three proteasomal regulatory mechanisms mentioned above, resulting in functional changes in cardiac proteasomes. Many lines of evidence support the important role of the ubiquitin-proteasome system (UPS) in the development of heart diseases. Many researchers have focused on the UPS, applying new drug discovery methods not only in the field of cancer research but also in cardiovascular fields such as cardiac hypertrophy and ischaemic heart diseases. More understanding of UPS in the pathophysiology of heart diseases will lead to new routes for therapy.