Compounds that inhibit the catalytic activity of cyclic nucleotide phosphodiesterases are used as therapeutic agents to increase intracellular cAMP and/or cGMP content in cells or tissues of interest. In patients with heart failure, inhibitors of enzymes in the PDE3 family of cyclic nucleotide phosphodiesterases are used to raise intracellular cAMP content in cardiac muscle, with inotropic actions. These drugs are effective in acute applications, but their long-term use has been complicated by an increase in cardiovascular mortality in clinical trials. Inhibitors of enzymes in the PDE5 family have been used to raise cGMP content in cardiac muscle in animal models of pressure overload, chronic β-adrenergic receptor stimulation, ischemic injury, and doxorubicin toxicity, and have been shown to have antihypertrophic and cardioprotective actions. Recent experimental results raise some question as to the likely applicability of these findings to humans, in whose hearts PDE5 is present at much lower levels than those seen in animal models, and raise the possibility of PDE1, a dual-specificity phosphodiesterase present at high levels in human myocardium, as an alternative target for inotropic and cardioprotective actions.