The 26S proteasome is a multicatalytic threonine protease complex responsible for degradation of the majority of proteins in eukaryotic cells. In the last two decades, the ubiquitin proteasome system (UPS) has been increasingly recognized as an integral component in numerous biologic processes including cell proliferation, adaptation to stress, and cell death. The turnover of intracellular proteins inevitably affects the contributions of these molecules to cellular networks and pathways in any given tissue or organ, including the myocardium. Perturbations in the protein-degradation process have been shown to affect protein turnover and thereby affect the cardiac cell functions that these molecules are designated to carry out, engendering diseased cardiac phenotypes. Recent studies have implicated the role of proteasomes in stressed cardiac phenotypes including postischemia–reperfusion injury and cardiac remodeling (e.g., heart failure). The 26S proteasomes also appear to be susceptible to modulation by stresses (e.g., reactive oxygen species). This review focuses on roles of the 26S proteasome system in protein degradation; it provides an overview of the progress made in cardiac proteasome research as well as a discussion of recent controversies regarding the UPS system in diseased cardiac phenotypes.