A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE) selectively in the brain. PDE3 inhibitors can be thought of as a backdoor approach to cardiac stimulation, whereas β-agonists go through the front door to produce the same cardiac effects. PDE3 was identified as a potential therapeutic target in cardiovascular disease and asthma, and indeed, PDE3 inhibitors have subsequently been shown to relax vascular and airway smooth muscle, inhibit platelet aggregation and induce lipolysis. It was recognised that papaverine and pentoxifylline mediated vasorelaxation by a number of mechanisms including non-selective PDE inhibition and these drugs can be considered as forerunners to the clinically successful PDE5 inhibitors used today for the treatment of erectile dysfunction. Phosphodiesterase inhibitors (PDIs) have important vascular and myocardial protective effects and thus have shown therapeutic usefulness in the clinical settings for treatment of patients with heart failure, pulmonary hypertension, and coronary artery disease. By increasing our understanding of the physiological roles of the individual PDE isoforms, in parallel with the development of even more selective inhibitors of these enzymes, it is highly likely that better therapeutically active drugs will emerge.