Soluble guanylate cyclase (sGC; EC 4.6.1.2), a heme-containing heterodimer, is the only proven receptor for the gaseous ligand NO and plays a crucial role in the NO/cGMP signaling pathway and downstream functional effects, e.g., vasorelaxation, platelet aggregation, or neurotransmission. Activation of the enzyme by NO leads to a five coordinated heme–nitrosyl complex, and facilitates conversion of GTP to the intracellular second messenger cGMP. It is this latter molecule cGMP, which mediates the majority of biological actions attributed to NO. sGC is expressed in virtually all mammalian cells and is important in mediating numerous physiological processes, including vascular and non-vascular smooth muscle relaxation, peripheral and central neurotransmission, platelet reactivity and phototransduction.