Products of the Neuregulin-1 (Nrg-1) gene, along with the ErbB family of receptor tyrosine kinases through which Nrg-1 ligands signal, play a critical role during cardiovascular development. Through studies of genetically manipulated mice, as well as studies in cells isolated from adult hearts, it appears that Nrg-1/ErbB signaling is an essential paracrine mediator of cell–cell interactions that not only regulates tissue organization during development, but also helps to maintain cardiac function throughout an organism's life. Studies in cells isolated from the heart demonstrate that Nrg-1 can activate a number of signaling pathways, which mediate cellular adaptations to stress in the myocardium. These observations provide insight as to why ErbB2-targeted cancer treatments have deleterious effects on cardiac function in some cancer patients. Moreover emerging data suggest that Nrg-1 ligands might be useful clinically to restore cardiac function after cardiac injury. In this review we will attempt to synthesize the literature behind this rapidly growing and exciting area of research.