The natriuretic peptides ANP, BNP and CNP are cardiac autacoids exerting local actions in the heart and, in the case of ANP and BNP, endocrine actions on the peripheral vasculature and kidneys. The major actions of the peptides are brought about by binding to membrane-bound receptors (NPR-1 and NPR-2), leading to activation of particulate guanylate cyclase and elevation of intracellular cGMP (Baxter, 2004). Accumulating evidence suggests that the natriuretic peptide/cGMP pathway may be an important autocrine/paracrine mechanism that attenuates both the extent of acute injury during infarction and the long-term proliferative responses relevant to the development of post-infarct cardiomyopathy (D’Souza et al., 2004). During acute myocardial ischaemia, tissue release of BNP is observed to be marked and rapid, consistent with an endogenous cardioprotectant role of the peptide. Recent evidence suggests that exogenously administered ANP and BNP are cardioprotective in a variety of ischaemia-reperfusion models. For example, ANP is anti-arrhythmic in coronary artery occlusion models and both ANP and BNP limit infarct size when administered prior to coronary occlusion. These protective effects are clearly related to elevation of cGMP concentration but the distal effectors of the survival signalling cascade are unclear. We have proposed that cGMP-dependent protein kinase (PKG) is a salvage kinase at reperfusion and demonstrated that pharmacological inhibition of PKG abrogates the infarct-limiting effect of postconditioning. More recently we have observed that BNP (10 nM) administered during the early reperfusion period limits infarct size, serving as a pharmacological mimetic of ischaemic postconditioning. Further work has revealed that the protective action of BNP at reperfusion is dependent on the opening of KATP channels since pharmacological inhibition with glibenclamide, 5-hydroxydecanoate or HMR1098 abrogates the protective action of BNP. Whether or not endogenous natriuretic peptides play a role in ischaemic postconditioning remains to be determined. Nevertheless, evidence such as that outlined above suggests that therapeutic activation of the natriuretic peptide/cGMP pathway may have potential to limit infarct size by salvaging myocardium from the injurious consequences of reperfusion. Following infarction, during the proliferative remodelling phase, the steady elevations of circulating ANP and BNP correlate with the extent of left ventricular dysfunction. The induction of natriuretic peptide production and release as a feature of the neurohormonal response is now well appreciated, and it seems likely that the peptides play local autocrine/paracrine roles that counter-regulate the proliferative signalling activated by angiotensin-II, catecholamines and endothelin. Although upregulation of ANP and BNP gene expression is a feature of cardiac myocyte hypertrophy, the peptides exert a marked anti-hypertrophic action in myocytes in vitro. There is also experimental evidence that cardiac fibroblasts may be a major source of ANP and BNP in remodelling, and that via a cGMP-dependent mechanism natriuretic peptides inhibit fibroblast proliferation and collagen synthesis. The effects of ANP and BNP on cardiac myocyte apoptosis are less clearly defined but these actions might also favourably influence remodelling. Recent work identifying the heart as a source of CNP during the evolution of heart failure raises questions about the possible autocrine/paracrine roles of this peptide and how these relate to the actions of ANP and BNP. Ultimately, the balance of proliferative and anti-proliferative signals will determine the extent of adverse remodelling and the natriuretic peptide family is likely to be very important in providing physiological antagonism of proliferative neurohormones. The reasons why there is apparent overwhelming of the beneficial effects of natriuretic peptide signalling in progressive hypertrophy and decompensation are unknown and represent a challenge for harnessing of the peptides’ therapeutic potential.