Cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) are second messengers involved in the intracellular signal transduction of a variety of extracellular stimuli in several tissues. In the vascular system, these nucleotides play important roles in the regulation of vascular tone and in the maintenance of the mature contractile phenotype in smooth muscle cells. Given that cyclic nucleotide signaling regulates a wide variety of cellular functions, it is not surprising that cyclic nucleotide phosphodiesterases (PDEs). In paticular, the accumulating data showing that there are a large number of different PDE isozymes have triggered an equally large increase in interest about these enzymes. At least 11 different gene families of PDEs are currently known to exist in mammalian tissues. Most families contain several distinct genes, and many of these genes are expressed in different tissues as functionally unique alternative splice variants. This article reviews many of the important aspects about the structure, cellular localization, and regulation of each family of PDEs. Particular emphasis is placed on new information obtained in the last few years about vascular disease. The development of novel methods to deliver more potent and selective PDE inhibitors to individual cell types and subcellular locations will lead to new therapeutic uses for this class of drugs in diseases of the vascular system.