The understanding of guanylyl cyclase regulation by nitrovasodilators has provided a great deal of information explaining the mechanisms of action of these cardiovascular drugs that have been in clinical use for the past century. The biochemical characterization of guanylyl cyclases and their regulation by NO have also permitted us, and others, to understand the mechanism of action of endothelium-dependent vasodilators and, subsequently, the roles for the nitric oxide-cyclic GMP signal transduction system in numerous cells and tissues. The potential importance of this signal transduction cascade is probably not fully appreciated since numerous additional studies obviously need to be performed. Also, as in many areas of science, serendipitous experiments and observations have added critical data to our present understanding in this field.