The adult heart is a post-mitotic terminally differentiated organ; therefore, beyond development, cardiomyocyte cell death is maladaptive. Heart disease is the leading cause of death in the world and aberrant cardiomyocyte cell death is the underlying problem for most cardiovascular-related diseases and fatalities. In this chapter, we will discuss the different cell death mechanisms that engage during normal cardiac development, aging, and disease states. The most abundant loss of cardiomyocytes occurs during a myocardial infarction, when the blood supply to the heart is obstructed, and the affected myocardium succumbs to cell death. Originally, this form of cell death was considered to be unregulated; however, research from the last half a century clearly demonstrates that this form of cell death is multifaceted and employees various degrees of regulation. We will explore all of the cell death pathways that have been implicated in this disease state and the potential interplay between them. Beyond myocardial infarction, we also explore the role and mechanisms of cardiomyocyte cell death in heart failure, myocarditis, and chemotherapeutic-induced cardiotoxicity. Inhibition of cardiomyocyte cell death has extensive therapeutic potential that will increase the longevity and health of the human heart.