Mammalian cells are constantly bathed in, and enveloped by, a mixture of naturally occurring gases. Whilst the biological significance of oxygen (O2) and carbon dioxide (CO2) in regulating cell function has been recognized for many centuries the possibility that other naturally occurring gaseous compounds may be synthesized from, and affect the function of, cells is a more recent phenomenon. To date, several biologically active gases have been identified and characterised. These include nitric oxide (NO) synthesized from L-arginine by nitric oxide synthase (NOS1, NOS2, NOS3) and carbon monoxide (CO) synthesized from haem by the enzyme, haem oxygenase (HO1 and HO2). NOS and HO enzymes are widely distributed in the body. NOS1, NOS3 and HO2 are constitutive enzymes whilst NOS2 and HO1 are induced in target tissues by a number of pathophysiological triggers. Recently a third gaseous mediator, hydrogen sulphide (H2S), has been added to this list. H2S is synthesized from L-cysteine by cystathionine β synthetase (CBS) and cystathionine γ lyase (CSE). Both CBS and CSE, previously considered as constitutive enzymes involved in the transsulphuration interconversion of L-methionine and L-cysteine/L-homocysteine, can also be induced in cells/tissues in certain disease states. Other potential biologically active gases include ammonia and sulphur dioxide (SO2) – a recently discovered natural product of endothelial cell metabolism. NO, CO and H2S exhibit a number of biological effects in common. In particular, all three gases dilate blood vessels and have been proposed to play physiological roles in the control of tissue vascular perfusion and pathophysiological significance with respect to, for example, vascular diseases such as hypertension, angina, myocardial infarction as well as inflammatory states such as shock and arthritis. Furthermore, all three gases exert complex effects on cell survival. Thus, NO can either cause or protect against cell death whilst CO is generally protective. H2S promotes cell death perhaps by inhibiting cytochrome c oxidase or by promoting apoptosis following activation of p38 MAP kinase or as a result of a genotoxic effect and concomitant p53 activation. All three gases also play a prominent part in inflammation and tissue injury. Once again, the effect of NO is complex with both pro- and anti-inflammatory activity reported depending on the model of inflammation and the time course of the inflammatory response. Intriguingly, H2S may also exhibit both pro- and anti-inflammatory activity. For example, both CSE inhibitors such as DL-propargylglycine (PAG) and slow releasing H2S donors such as S-diclofenac reduce lipopolysaccharide-evoked endotoxic shock (Li et al., 2005; Li et al., 2007). Numerous examples of ‘cross talk’ between these three gases have been identified. Such interactions can take place at the level of transcriptional control of synthesizing enzymes, actions on transduction mechanisms mediating biological effects and direct chemical reactions. For example, NO downregulates HO1 and CSE expression in isolated cells and in intact animals. In turn, H2S inhibits NO production and NF-kB activation in lipopolysaccharide-stimulated macrophages by a mechanism which involves activation/upregulation of HO-1 and release of CO (Oh et al., 2006). In stark contrast, H2S has been reported to decrease HO-1 expression in cultured smooth muscle cells. Aside from these interactions at the transcriptional and/or translational level there are additional reports that NO either augments or reduces the vasorelaxant effect of H2S and vice versa. In addition, we have recently reported that H2S interacts with NO to form an as yet unidentified nitrosothiol moiety. This mechanism may perhaps explain the ability of H2S to further contract isolated precontracted rat aortic rings and to rapidly reverse the relaxation of aortic rings in response to both acetylcholine and sodium nitroprusside (SNP). Interestingly, mixing H2S with SNP completely abolished the vasodepressor effect of SNP in anaesthetised rats suggesting that the interaction takes place both in vitro and in vivo (Ali et al., 2006). As progress in our understanding of the biological significance of NO, CO and H2S increases at a rapid rate it is becoming more clear that a complete understanding of the effect of these gases on cell/tissue function demands a truly integrated approach to their study. Bearing in mind the interactions between these gases already identified and the possibility that other gases may also be involved we may have to concede that it is now no longer possible to ‘get the full picture’ simply by evaluating the effect of a single gas on any particular biological system.