The magnitude of an acute myocardial infarction (MI; i.e., number of dead cardiomyocytes) is the most critical determinant of subsequent left ventricular remodeling and heart failure. Also affecting the post-infarction disease process, however, are events occurring during the subacute and chronic stages of the infarction, including late cardiomyocyte death, cardiomyocyte hypertrophy, fibrosis, and expression of various cytokines. Additionally, it has been suggested that apoptosis may be responsible for a significant amount of cardiomyocyte death during the acute ischemic stage, as well as for a progressive loss of surviving cells during the subacute and chronic stages. However, there is very little direct morphological evidence of apoptosis occurring at any stage of MI, despite the availability of much indirect evidence that includes detection of DNA fragmentation and apoptosis-related factors. For that reason, the potential efficacy of therapeutic intervention to prevent apoptosis remains controversial. This review will survey available data from both animals and humans to critically assess the role of cardiomyocyte apoptosis during MI and its relevance to myocardial remodeling and heart failure. Also considered will be nonmyocyte interstitial cells, which have received less attention than myocytes despite definitive evidence of their apoptosis in the infarcted heart and recent studies suggesting that blockade of apoptosis among these cells mitigates post-infarction cardiac remodeling and heart failure. We conclude from our survey that there are many hurdles to surmount before regulation of apoptosis can be clinically applied in the treatment of MI and other heart diseases.