Apoptosis plays an important role in various cardiovascular diseases, and inhibition of cardiac apoptosis shows promise as a therapeutic strategy. Caspase, a critical enzyme in the induction and execution of apoptosis, has been targeted to inhibit apoptosis. However a newly recognized caspase-independent apoptosis pathway may also play an important role in cardiac apoptosis. Yet the mechanism and the potential significance of caspase-independent apoptosis in the heart remain poorly understood. In this paper, we reviewed the literatures on the mechanism of caspase-independent apoptosis and its significance in cardiovascular diseases.