Loss of cardiac function following myocardial infarction (MI) remains a leading cause of morbidity in the developed world. Current percutaneous coronary intervention (PCI) practice facilitates rapid relief of acute thrombotic occlusion with follow on medical treatment of associated atherosclerotic and thrombotic risks, late ventricular remodeling and cardiac arrhythmias. The application of regenerative therapies aimed at preserving or restoring lost myocardial function post large MI is currently evolving. In the early phase of myocardial reperfusion post PCI, cardiomyocyte apoptosis occurs followed closely by pro-inflammatory cell infiltration from the circulation. At later timepoints, matrix protein deposition and scar formation become evident followed by later loss of functioning cardiomyocyte cell mass leading to a dilated failing heart. In the last decade, clinical trials have assessed the ability of therapy using progenitor cells from various tissue niches to prevent or reverse these effects in the post-reperfusion phase. Modest improvements in hemodynamic function reported in many (but not all) of these trials have tempered initial optimism for cardiac regenerative therapeutics. In addition, several issues concerning cardiac cell therapy including efficacy, quality assurance, necessary infrastructure, effective translation of preclinical studies and applicability to broader patient care, have been raised. Fortunately, a number of promising derivative therapeutic strategies have also emerged including stem cell derived paracrine factors and recent advances in tissue engineering. In this review, the ability of stem cells and/or derivative therapies to modify apoptosis and inflammation in the ischemic zone are considered along with emerging cell and tissue engineering approaches toward cardiac regeneration post-MI.