The second messengers cyclic 3′,5′ adenosine monophosphate (cAMP) and cyclic 3′,5′ guanosine monophosphate (cGMP) play a key role in mediating a variety of functional responses to hormones and other cellular transmitters. Phosphodiesterases (PDEs) are intracellular enzymes that specifically catalyze the hydrolysis of these second messengers. By counterbalancing the enzymes adenylyl cyclase and guanylyl cyclase, which catalyze the formation of cAMP and cGMP, respectively, they regulate the intracellular concentration of both second messengers, thereby influencing a broad variety of physiological functions. PDEs belong to a large superfamily (11 different gene families encode for the PDE families PDE1 to PDE11) of structurally related, functionally distinct, and highly regulated enzymes. Owing to their key roles in physiological processes, PDEs are targets for many drugs that are used for different diseases, such as cardiovascular diseases, asthma, erectile dysfunction (ED), and many others. Increasing knowledge of the molecular biology, regulation, and tissue distribution of this class of enzymes has led to a better understanding of the physiological function of cyclic nucleotides and of the regulatory role of PDEs. This progress was supported by the development of potent PDE inhibitors that are highly selective for one PDE family. Prominent examples are the newly developed selective PDE5 inhibitors, which are discussed here, used for the effective oral treatment of ED.