NO-sensitive guanylyl cyclase (NO-GC) acts as the receptor for nitric oxide and by the increase in cGMP executes most of the NO effects in the cardiovascular and neuronal system. Two isoforms of NO-GC exist whose existence has not been paid much attention to probably because they reveal comparable regulatory and catalytic properties and therefore cannot be differentiated in vivo. Analysis of mice in which either one of the isoforms has been genetically deleted unequivocally establishes the coexpression of NO-GC1 and NOGC2 in any tissue tested to date with the exception of platelets. In tissues other than brain and platelets, no particular function could be ascribed to a specific NO-GC isoform so far. In contrast, NO-GC1 and NO-GC2 serve different functions in the central nervous system. With NO-GC1`s presynaptic role and NO-GC2`s postsynaptic action, two NO/cGMP pathways have been shown to exist that enhance the strength of synaptic transmission on either side of the synaptic cleft.