Nitric oxide regulation of the cardiovascular system involves both cGMP-dependent and independent mechanisms. The former directly interacts with the family of catabolic phosphodiesterases (PDEs) that control cGMP levels and thus distal effects such as protein kinase G stimulation. Growing evidence supports an important role of several PDEs, including PDE1, PDE2, and PDE5, in the regulation of cGMP in both vascular smooth muscle and cardiac myocytes. These PDEs have relatively little impact on resting function, but they can potently modulate acute contractile tone in cells stimulated by external agonists such as angiotensin or catecholamines. Regulation by PDEs is compartmentalized, with selective interactions occurring between a given source of cGMP and PDE hydrolysis. PDE1 and/or PDE5 are also reportedly up-regulated in chronic disease conditions such as atherosclerosis or cardiac pressure-load stress and heart failure as well as in response to long-term exposure to nitrates. Such up-regulation is thought to contribute to vascular and cardiac pathophysiology and to drug tolerance. Recent studies utilizing selective PDE5 inhibitors support significant cross-signaling with NO–cGMP synthetic pathways that may be particularly helpful in treating certain disease states.