The NO/cGMP-mediated platelet signaling pathways. NO activates cGMP synthesis by sGC. cGMP induces activation of cGKI and inhibition of PDE3, which lead to stimulation or inhibition of platelet activation. The novel cGKI-dependent platelet inhibition mechanism described in this issue of Blood involves cGK phosphorylation of IRAG, which negatively regulates InsP₃ receptor (InsP₃R)–dependent calcium elevation, and thus causes inhibition of platelet activation. Illustration by Marie Dauenheimer.