Maintenance of protein quality control is a critical function of the ubiquitin proteasome system (UPS). Evidence is rapidly mounting to link proteasome dysfunction with a multitude of cardiac diseases, including ischemia, reperfusion, atherosclerosis, hypertrophy, heart failure, and cardiomyopathies. Recent studies have demonstrated a remarkable level of complexity in the regulation of the UPS in the heart and suggest that our understanding of how UPS dysfunction might contribute to the pathophysiology of such a wide range of cardiac afflictions is still very limited. Whereas experimental systems, including animal models, are invaluable for exploring mechanisms and establishing pathogenicity of UPS dysfunction in cardiac disease, studies using human heart tissue provide a vital adjunct for establishing clinical relevance of experimental findings and promoting new hypotheses. Accordingly, this review will focus on UPS dysfunction in human dilated and hypertrophic cardiomyopathies and highlight areas rich for further study in this expanding field.