The discovery that degradation and inactivation of the second messengers cAMP and cGMP are mediated by a complex enzymatic machinery has changed our perspective on cyclic nucleotide-mediated processes. In the cell, these second messengers are inactivated by no fewer than 11 distinct families of phosphodiesterases (PDEs). Much is known about the structure and function of these enzymes, their complex subcellular distribution and regulation. Yet, their potential as targets for therapeutic intervention in a broad range of endocrine abnormalities still needs to be investigated. This review explores the involvement of PDEs in the regulation of intracellular signaling and focuses on the known and potential roles that are of interest to endocrinologists.