The activity of phosphodiesterases (PDEs) is associated with a wide variety of diseases and an intense effort toward the development of specific PDEs inhibitors has been generated for the last years. They are the enzymes responsible for the hydrolysis of intracellular cyclic adenosine and guanosine monophosphate, and their complexity, as well as their different functional role, makes these enzymes a very attractive therapeutic target. This review is focused on the role of PDEs played on immunomodulatory processes and the advance on the development of specific inhibitors, covering PDEs mainly related to the regulation of autoimmune processes, PDE4 and PDE7. The review also highlights the novel structural classes of PDE4 and PDE7 inhibitors, and the therapeutic potential that combined PDE4/PDE7 inhibitors offer as immunomodulatory agents.