Soluble guanylate cyclase (sGC) facilitates the conversion of guanosine-5’-triphosphate to cyclic guanosine-3’,5’-monophosphate (cGMP) and regulates many aspects of cell function through activation of specific kinases, ion channels and phosphodiesterases. The role of sGC as the principal receptor for nitric oxide (NO) is well-established and known to be fundamental to the physiological regulation of numerous organ systems. Consequently, dysfunctional NO/sGC signalling has been implicated in the aetiology of an array of pathologies. Yet, NO may not represent the sole endogenous ligand for sGC. This is illustrated by the fact that triple NO synthase knockout mice are viable whereas genetic deletion of the β₁ subunit of sGC is lethal, implying that animals unable to synthesise NO can still utilise cGMP-dependent pathways. Accordingly, recent evidence suggests that alternate, endogenously-generated gaseous signalling species, such as carbon monoxide (CO) and hydrogen sulphide (H₂S), may also exert their biological effects (at least in part) via activation of sGC. In comparison to NO, the biological chemistry of CO is simple in that it forms coordination complexes with metalloproteins, but will not react with O₂, and is therefore relatively stable in most cellular environments. The majority of endogenous CO synthesis originates from the action of haem oxygenase (HO) enzymes that oxidise ‘free’ haem resulting in the generation of CO, iron and biliverdin. Indeed, it is the complexity and chemical difficulty in generating CO in this manner strongly suggests that CO is deliberately synthesised, rather than a just a noxious waste product. Despite the fact that the degree of activation of purified sGC by CO is miniscule compared to NO (~4-fold versus ~200-fold), many biological effects of CO appear to be mediated via sGC, since they are sensitive to the selective inhibitor, ODQ. This holds true for the majority of smooth muscle relaxant, neurotransmitter, anti-inflammatory and anti-platelet properties of CO. Moreover, synergistic interaction of allosteric sGC activators (e.g. YC-1, BAY 41-2272) with CO implies that under some circumstances sGC may become hyperresponsive to CO. This may be most apparent during pathological episodes characterised by oxidative stress (when NO bioactivity is negated due to reactions with O₂-derived species) in which CO will retain chemical stability and may help maintain sGC-dependent signalling. Under these conditions, oxidation of specific cysteine residues in the enzyme that contribute to the allosteric sGC activator binding site, will potentially increase the responsiveness of the enzyme to CO. H₂S is the simplest thiol species present in biological systems and physiological levels of H₂S are relatively high (compared to NO and CO), reaching ~150μM. The major routes of H₂S biosynthesis are via the enzymes cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE), that are highly-expressed in the CNS and vasculature, respectively. Whilst H₂S is unlikely to form a complex with the haem-iron of sGC and activate the enzyme in a manner akin to NO and CO, data suggest that H₂S interacts with NO-dependent signalling, both at the level of sGC and NO synthase. Moreover, the appreciated importance of reduced cysteine residues in sGC in maintaining NO sensitivity, may suggest that H₂S can act as a physiological reductant to preserve cGMP-dependent signalling. This is supported by the reports that CBS and CSE activity is augmented by NO, suggesting that NO and H₂S are generated concomitantly. Further still, direct interaction of H₂S and NO under appropriate conditions, may result in the formation of the simplest S-nitrosothiol (HSNO), that could act as a means to protect NO from oxidative destruction. Considered together, the above observations give rise to the possibility that NO, CO and H₂S coordinate to preserve the (principally) cytoprotective effects of cGMP. In turn, this suggests that sGC is ideally placed to act as an endogenous ‘redox sensor’ and adapt its sensitivity to these gaseous signalling species to optimise cGMP-dependent signalling. A better understanding of the actions and interactions of NO, CO and H₂S is likely to identify novel targets for therapeutic intervention.