Since the discoveries that have verified nitric oxide (NO) as an endogenously produced cell signaling molecule, research surrounding its production and mechanisms of action have been studied at an exponentially increasing rate. NO is produced by a family of enzymes termed the NO synthases (NOS), which are regulated independently by various stimuli. Once produced, NO can solicit numerous biological events by reacting with various metals, thiols, and oxygen species to modify proteins, DNA and lipids. One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3',5'-cyclic guanosine monophosphate (cGMP), which can regulate numerous physiological events such as vasodilatation and neurotransmission. Here we will review the synthesis and fate of NO, and discuss the activation and regulation of the NO receptor, sGC.