Proteolysis within the cardiac sarcomere is a constantly evolving area of research. Three major pathways of proteolysis have been identified as being active within the cardiac sarcomere, namely the ubiquitin-proteasome system, autophagy, and the calpain system. The role of ubiquitin-proteasome system-mediated proteolysis in cardiovascular health and disease has been known for some time; however, it is now apparent that other proteolytic systems also aid in the stabilization of cardiac sarcomere structure and function. This minireview focuses on the individual as well as cooperative involvement of each of these three major pathways of proteolysis within the cardiac sarcomere.