Cyclic adenosine 3′-5′-monophosphate (cAMP) and cyclic guanosine 3′-5-monophosphate (cGMP) are two critical intracellular second messengers provided with strong inhibitory activity on fundamental platelet activation pathways. Phosphodiesterases (PDEs), an almost ubiquitous class of enzymes able to break phosphodiester bonds, reduce the intracellular levels of cyclic nucleotides in cells by catalyzing the hydrolysis of cAMP and cGMP, and this in platelets regulates activation. The inhibition of PDEs may therefore exert a strong platelet inhibitory effect by increasing cAMP and cGMP. In mammalian tissues, 11 structurally related but functionally distinct PDE gene families (PDE1-11) have been described and, given their involvement in many physiological and pathological phenomena, they have been the object of intense pharmacological research. Platelets possess three PDE isoforms: PDE2, PDE3, and PDE5, with different selectivity for cAMP and cGMP. Several non-selective or isoenzyme-selective PDE inhibitors have been developed and some of them have entered clinical use as antiplatelet agents. A few also display adenosine-reuptake inhibitory properties, thus increasing the circulating levels of adenosine, a nucleoside provided with strong vasodilatory and platelet inhibitory effects. This review will focus on the effects of PDE2, PDE3, and PDE5 inhibitors on platelet function, and on the available evidence for an antithrombotic action of some of them, and in particular of dipyridamole and cilostazol. This is an update of the previous chapters from the 2017 edition of the book and parts have been reused, https://link.springer.com/book/10.1007/978-3-319-47462-5 .