NO and cGMP constitute an autocrine, paracrine, and possible endocrine signal transduction system. Cytosolic NO-responsive guanylyl cyclase can be stimulated by NO derived from its own cell, from similar or distinct neighboring cell types within a tissue, from a circulating pool of NO (as NO+ equivalents coupled to plasma protein thiol groups), or from pharmacologic agents, the nitrovasodilators. NO and cGMP together comprise an especially wide-ranging signal transduction system when one considers (i) the many roles of cGMP in physiological regulation, including smooth muscle relaxation, visual transduction, intestinal ion transport, and platelet function; (ii) the many sources, biochemical interactions, and functions of NO; and (iii) the interactions of cGMP and its affected pathways with other signaling systems such as phosphoinositides, eicosanoids, cAMP and Ca2+.