Phosphodiesterase-5 (PDE5) inhibitors have been approved by the US Food and Drug Administration for the treatment of erectile dysfunction and more recently for pulmonary arterial hypertension (World Health Organization functional class I). PDE5 inhibitors can induce vasodilation; in addition, through a complex pathway involving nitric oxide, cyclic guanosine monophosphate, and protein kinase G, it can reduce apoptosis and suppress cell proliferation. The presence of PDE5 inhibitors in various tissues and systemic vasculature make them potential targets in a variety of cardiovascular diseases. In many in vitro and in vivo studies, PDE5 inhibitors have been shown to have positive effects in systolic and diastolic congestive heart failure, ischemic heart disease, doxorubicin cardiomyopathy, and pulmonary arterial hypertension. They also improved vasoconstriction in Raynaud phenomenon, peripheral artery disease, and hypoxic brain conditions. This article reviews the therapeutic potentials of PDE5 inhibitors in different cardiovascular diseases.