ABSTRACT The proteasome mediates the degradation of most cellular proteins including misfolded proteins, pivotal to intracellular protein hemostasis. Proteasome functional insufficiency is implicated in a large subset of human failing hearts. Experimental studies have established proteasome functional insufficiency as a major pathogenic factor, rationalizing proteasome enhancement as a potentially new therapeutic strategy for congestive heart failure. Protein kinase G activation known to be cardioprotective was recently found to facilitate proteasomal degradation of misfolded proteins in cardiomyocytes; sildenafil was shown to activate myocardial protein kinase G, improve cardiac protein quality control and slow down the progression of cardiac proteinopathy in mice. This identifies the first clinically used drug that is capable of benign proteasome enhancement and unveils a potentially novel cardioprotective mechanism for sildenafil.