The removal of damaged or unwanted proteins from cardiac muscle cells is essential to maintain optimal heart function. Removal of these “junk” proteins occurs at specific locations within cardiac muscle cells, including cell-cell junctions, and requires the action of certain enzymes that reside within these cellular compartments. When these enzymes relocate to other regions within the cell and continue the removal process, irregular protein turnover occurs which can disrupt cellular function. Here we discuss the role that the relocation of protein removal enzymes plays in the development of cardiac diseases, and the potential for targeting these enzymes as a therapeutic approach for cardiac disease.