Over the past decade the cardiovascular regenerative medicine field has made significant advances in our understanding and treatment of injured myocardium. Prior to stem cell therapy, available treatments for cardiovascular disease were unable to repair or regenerate the damaged heart. Stem cell therapy is increasingly becoming a viable option to prevent and treat cardiac dysfunction. A number of exogenous stem cell populations have been examined for their ability to participate in cardiac repair. Their application in the clinical setting will be reviewed here. The molecular pathways that work in concert to orchestrate a systemic endogenous stem cell response to cardiac injury have also begun to be defined. A potential strategy for future therapeutics is the manipulation of these endogenous pathways via pharmacological or biopharmaceutical approaches. In this review we begin to formulate the discussion that the best future therapeutic option to regenerate end organ function will be a combination of programmed stem cells and biopharmaceuticals that modulate regenerative signaling to bolster the natural in vivo cellular and signaling mechanisms.