The traditional model of efferent cardiac noradrenaline and acetylcholine release being driven solely via brainstem integration of circulatory reflex afferent input needs to be modified in the light of the discovery of numerous local cardiac factors that impact on peripheral neuronal neurotransmitter release. These neuromodulators can be intrinsic to sympathetic ganglia or vagal neurons (such as neuronal nitric oxide synthase), act as cotransmitters between these neuronal populations (such as neuropeptide Y) or are released from the myocardium itself to act on neurons in a paracrine manner (such as natriuretic peptides). Both myocardial infarction and congestive heart failure are characterized by enhanced regulation of these neuromodulators. This review will focus on recent evidence that nitric oxide, natriuretic peptides and neuropeptide Y act by converging on neuronal cyclic nucleotide-dependent pathways to alter the autonomic phenotype in both health and disease.