Phosphodiesterases (PDE) are a class of proteins whose most relevant biological activity concerns the modulation of intracellular levels of cyclic nucleotides, e.g., cGMP and cAMP. PDE isoenzyme 5 (PDE5) is specifically involved in cGMP inactivation in the smooth muscle cell. Chemical inhibition of PDE5 by sildenafil, tadalafil or vardenafil recently became a valid therapeutic option aimed at overexpressing the molecular pathway originated from nitric oxide and expressed via increased cell cGMP availability. Based on the optimal tolerability and proven efficacy in various human disorders, EMEA and FDA have approved PDE5 inhibition as an efficient therapy in some cardiovascular, pulmonary and vascular diseases. More specifically, PDE5 inhibition appears successful for the treatment of idiopathic arterial pulmonary hypertension. Furthermore, PDE5 inhibition resulted in important protective effects in the myocardium, i.e., antyhypertrophic and antiapoptic, as well as vascular functions, i.e., increased tolerance to ischemia/reperfusion injury and improved endothelial function, thereby implying a potential usefulness in the treatment of patients with heart failure and coronary artery disease. Evidence currently available for considering PDE5-inhibition an additional opportunity in the treatment of common cardiopulmonary disorders is here provided.