Phosphodiesterase 5 (PDE5) is one of eleven members of the mammalian phosphodiesterase family that hydrolyzes cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP). Best known as the target of the impotence drug sildenafil, PDE5 degrades cGMP in smooth muscle cells so as to maintain the contracted state of contractile organs such as the penis, blood vessels, uterus, and intestines. In addition, it regulates numerous other physiological processes such as neurogenesis and apoptosis. Like all other PDEs, PDE5 is dimeric; each subunit is approximately 100 kd in size and has two allosteric cGMP-binding sites and a catalytic domain. Protein kinase G (PKG)-mediated phosphorylation and allosteric cGMP binding upregulate PDE5 activity, while PP1 phosphatase-mediated dephosphorylation downregulates. Sildenafil and other selective inhibitors inhibit PDE5 by binding to the catalytic site. From two promoters a single PDE5A gene at human chromosome 4q26 encodes three alternatively spliced isoforms (PDE5A1-3) that differ in the N-terminus. The PDE5A promoter is located upstream of the three isoform-specific first exons (in the order of A1-A3-A2) and consists of a 139-bp core, a 308-bp upstream enhancer, and a 156-bp downstream enhancer. The weaker 182-bp PDE5A2 promoter is located between the A3- and A2-specific exons and contains an indispensable Sp1-binding sequence. Both promoters are responsive to cGMP or cAMP stimulation, and several studies have demonstrated regulation of PDE5 expression possibly through these promoters. Virtually all tissues and cell types express PDE5, with heart and cardiomyocytes being contentious. PDE5A1 and PDE5A2 are ubiquitous, but PDE5A3 is specific to smooth muscle.