A growing body of animal studies provides evidence for potential cardioprotective effects of inhibitors of the enzyme phosphodiesterase isoform 5. Infarct size reduction by administration of phosphodiesterase 5 inhibitors was described in various experimental models of ischaemia and reperfusion. Furthermore, potential beneficial effects were demonstrated in experimental models of congestive heart failure and left ventricular hypertrophy. Some of the observed effects resemble the basic mechanisms of ischaemic pre-conditioning, mimicking both acute and delayed effects. Other effects may be due to action on systemic and cardiac haemodynamics. Mechanisms and signalling pathways, characterized in some of the experimental models, appear to be complex: for instance, the rate of cyclic guanosine monophosphate (cGMP) synthesis and the functional compartmentalization of intracellular cGMP metabolism as well as interaction with ss-adrenergic and nitric oxide signalling may influence effects in different experimental settings. In this review, we discuss mechanisms, signalling pathways, and experimental limitations and touch on considerations for translation into potentially useful applications in the clinical arena.