The NO/cGMP signalling cascade has an important role in smooth muscle relaxation, inhibition of platelet aggregation and neuronal transmission. Although the function of the main NO receptor GC (NO-GC) is well established, the particular tasks of the NO receptor isoforms (NO-GC1 and NO-GC2) are unclear and NO targets other than NO-GC have been postulated. Mice deficient in either NO receptor isoform or with a complete lack of NO-GC are now available and allow new insights in NO/cGMP signalling. The first reports about the KO strains show that, outside the neuronal system, the NO-GC isoforms can substitute for each other, and that amazingly low cGMP increases are sufficient to induce smooth muscle relaxation. In the neuronal system, however, the NO-GC isoforms obviously serve distinct functions as both isoforms are required for long term potentiation. Analysis of the complete NO-GC KO provides evidence that the vasorelaxing and platelet-inhibiting effects of NO are solely mediated by NO-GC. Thus, NO-GC appears to be the only NO receptor in these two systems.