Phosphodiesterases (PDEs) are metallohydrolases that control the concentration of second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate. Cyclic nucleotides are critical intracellular signaling molecules that are required for the proper function of the brain. All neurons express PDEs, and PDE inhibition represents a mechanism through which it could be possible to precisely modulate neuronal activity. The interest for PDEs as targets continues to grow within therapies to treat CNS diseases, particularly for cognitive dysfunction and neuropsychiatric diseases.