The intracellular messenger cyclic GMP (cGMP) represents the key signal in several transduction pathways throughout the animal world. In the heart cGMP signaling contributes to functional interaction of different cell types. Nitric oxide (NO) and natriuretic peptides (NPs), major autocrine-paracrine cardiovascular regulators, increment intracellular cGMP through guanylate cyclases (GCs). NO and NPs interact with two GC types: cytosolic (soluble: sGC) and membrane bound [particulate: pGC (NP receptor types A and B)], respectively. Depending on sub-cellular localization and regulation of the enzymes, cGMP produced by either pGC or sGC exerts different complementary effects. The two pathways are reciprocally regulated. NPsdepending pGC is modulated by NO-cGMP signaling, and the activity of NO is influenced by cellular concentrations of both NO itself and NPs. This heterologous feedback regulates GCs, linking cardiovascular autocrine-paracrine activities of NPs and NO. Importance of these cGMP converging routes goes far beyond their role under normal conditions. They are of relevance especially in disease states when tissue and circulating levels of NPs, and local NO production are altered. An example is the endothelial dysfunction associated with deficient NO production and uncoupled endothelium-myocardium communications. In this case, NPs-pGC-cGMP could supplement the reduced activity of NO-scGC-cGMP pathway. In addition, these systems regulate cell growth and apoptosis, playing a role in myocardial pathological morpho-functional remodeling. Here we will review recent concepts on NO/NPs dependent control of heart function in vertebrates, also focusing on cGMP-activated downstream signaling and its role in health and disease conditions.