Phosphodiesterase 5 (PDE5) has been identified in many species. The three isoforms, PDE5A1, PDE5A2, and PDE5A3, differ only in their N-terminal sequence. PDE5A1 and PDE5A2 are ubiquitous, but PDE5A3 is specific to smooth muscle. The initial three exons (A1-A3-A2) of PDE5A, located on chromosome 4q26, are alternative first exons encoding the isoform-specific sequences. The PDE5A promoter overlaps with the A1-specific exon, while the PDE5A2 promoter is located between the A3- and A2-specific exons. Both respond to cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate (cAMP) stimulation. The PDE5A2 promoter contains an Sp1-binding sequence critical for basal and cGMP/cAMP-inducible promoter activities. PDE5A is induced by adjacent sequences (enhancers) containing Sp1-binding sites. The potential role of PDE5A promoters in the tachyphylaxis effect of PDE5 inhibitors is currently being investigated. Preliminary data suggest that hypoxia might down-regulate PDE5A promoters, implying an involvement of PDE5 in stuttering priapism.