Since the discovery of nitric oxide (NO) formation in animals, it has become clear that this toxic, free radical, diatomic gas plays a central role in cellular function in eukaryotes. NO acts as a signaling agent in the cardiovascular system and other tissues. Using a low concentration of NO mitigates the toxicity problem but places a difficult chemical requirement on the NO receptor, the soluble isoform of guanylate cyclase (sGC). sGC contains a heme cofactor that binds and traps NO, thereby activating the enzyme to convert GTP to cGMP. The heme in sGC has unique ligand binding properties enabling sGC to act as a selective receptor for NO. The heme domain of sGC was found to be part of the H-NOX (Heme-Nitric oxide/Oxygen) family of proteins with homologues in both aerobic and anaerobic prokaryotes. Studies with H-NOX proteins has provided a molecular explanation for selective NO trapping at low concentrations. The structure/function picture that is emerging provides new clues to the activation mechanism. It is also become clear that the activation and deactivation of sGC is more complicated than the simple model of NO binding to the heme. As a physiological model is developed it must also account for activity properties of stimulators such as the FDA-approved Adempas®.