Cyclic guanosine 3',5'-monophosphate (cGMP) mediates a wide spectrum of physiologic processes in multiple cell types within the cardiovascular system. Dysfunctional signaling at any step of the cascade — cGMP synthesis, effector activation, or catabolism — have been implicated in numerous cardiovascular diseases, ranging from hypertension to atherosclerosis to cardiac hypertrophy and heart failure. In this review, we outline each step of the cGMP signaling cascade and discuss its regulation and physiologic effects within the cardiovascular system. In addition, we illustrate how cGMP signaling becomes dysregulated in specific cardiovascular disease states. The ubiquitous role cGMP plays in cardiac physiology and pathophysiology presents great opportunities for pharmacologic modulation of the cGMP signal in the treatment of cardiovascular diseases. We detail the various therapeutic interventional strategies that have been developed or are in development, summarizing relevant preclinical and clinical studies.