Phosphodiesterase type-5 (PDE-5) inhibitors including sildenafil, vardenafil and tadalafil are a new class of vasoactive drugs that have been developed for treatment of erectile dysfunction in patients. A growing number of studies in recent years suggest that sildenafil may be used clinically for treatment of pulmonary hypertension and endothelial dysfunction. In addition, recent studies primarily from our laboratory suggested that sildenafil has preconditioning-like powerful cardioprotective effect in the animal models of ischemia-reperfusion injury. Sildenafil has been found to exert cardioprotection through nitric oxide generated from endothelial and/or inducible nitric oxide synthases and opening of mitochondrial ATP-sensitive potassium channels. Future demonstration of the cardioprotective effect in patients with the relatively safe and effective FDA-approved PDE-5 inhibitors, such as sildenafil, could have an enormous impact on bringing the long-studied phenomena of ischemic and pharmacologic preconditioning to the clinical forefront.