The myocardium represents a major source of several families of peptide hormones under normal physiological conditions and the plasma concentrations of many of these "cardiac peptides" (or related pro-peptide fragments) are substantially augmented in many cardiac disease states. In addition to well-characterised endocrine functions of several of the cardiac peptides, pleiotropic functions within the myocardium and the coronary vasculature represent a significant aspect of their actions in health and disease. Here, we focus specifically on the cardioprotective roles of four major peptide families in myocardial ischemia and reperfusion: adrenomedullin, kinins, natriuretic peptides and the urocortins. The patterns of early release of all these peptides are consistent with roles as autacoid cardioprotective mediators. Clinical and experimental research indicates the early release and upregulation of many of these peptides by acute ischemia and there is a convincing body of evidence showing that exogenously administered adrenomedullin, bradykinin, ANP, BNP, CNP and urocortins are all markedly protective against experimental myocardial ischemia-reperfusion injury through a conserved series of cytoprotective signal transduction pathways. Intriguingly, all the peptides examined so far have the potential to salvage against infarction when administered specifically during early reperfusion. Thus, the myocardial secretion of peptide hormones likely represents an early protective response to ischemia. Further work is required to explore the potential therapeutic manipulation of these peptides in acute coronary syndromes and their promise as biomarkers of acute myocardial ischemia.