Drugs that inhibit cyclic nucleotide phosphodiesterase activity act to increase intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) content. In total, 11 families of these enzymes—which differ with respect to affinity for cAMP and cGMP, cellular expression, intracellular localization, and mechanisms of regulation—have been identified. Inhibitors of enzymes in the PDE3 family of cyclic nucleotide phosphodiesterases raise intracellular cAMP content in cardiac and vascular smooth muscle, with inotropic and, to a lesser extent, vasodilatory actions. These drugs have been used for many years in the treatment of patients with heart failure, but their long-term use has generally been shown to increase mortality through mechanisms that remain unclear. More recently, inhibitors of PDE5 cyclic nucleotide phosphodiesterases have been used as cGMP-raising agents in vascular smooth muscle. With respect to cardiovascular disease, there is evidence that these drugs are more efficacious in the pulmonary than in the systemic vasculature, for which reason they are used principally in patients with pulmonary hypertension. Effects attributable to inhibition of myocardial PDE5 activity are less well characterized. New information indicating that enzymes from the PDE1 family of cyclic nucleotide phosphodiesterases constitute the majority of cAMP- and cGMP-hydrolytic activity in human myocardium raises questions as to their role in regulating these signaling pathways in heart failure.