The prominence of phosphodiesterase-5 (PDE-5) inhibitors in the treatment of male erectile dysfunction and other diseases related to vascular dysfunction mandates a comprehensive understanding of the properties and effects of these compounds. Three potent and selective PDE-5 inhibitors (sildenafil, tadalafil, and vardenafil) have been approved for clinical use. The clinical efficacy and safety profiles of these medications are related to their molecular mode of action, the selectivity for PDE-5, and the pharmacokinetic properties (absorption, bioavailability, time to onset of action, distribution, metabolism, and elimination). These PDE-5 inhibitors share some common properties with regard to mechanisms of action and selectivities for PDE-5. They also have distinctive characteristics that may impact their clinical use. This article focuses on the basic biochemistry of cyclic guanosine monophosphate signaling and the pharmacokinetic parameters that describe characteristics of drug action of these PDE-5 inhibitors in facilitating smooth muscle relaxation, leading to improved penile erectile response or causing side effects.