Hydrogen sulfide (H2S) is the latest addition to the gasotransmitter family, that also includes nitric oxide (•NO) and carbon monoxide (CO). As with NO and CO, initially, the majority of publications on H2S focused on the toxicological profile of this gasotransmitter, with the general bioscience community shown only a very limited interest in the biology of H2S. Proof for endogenous production of H2S in mammalian cells, along with observations that H2S acts as a neuromodulator and vasorelaxing agent sparked the interest for this diatomic molecule. H2S is now recognized as a signaling molecule, with important functions in cell metabolism, growth and apoptosis. Moreover, H2S modulates inflammatory responses, regulates vascular smooth muscle tone, promotes angiogenesis and reduces blood pressure. The prototype gasotransmitter NO, also exhibits many of the above-mentioned properties. Although initially, ATP-sensitive K+ channels were thought to be the main mechanism through which H2S exerts its cardiovascular effects, cGMP and protein sulfhydration are increasingly being shown to contribute to the actions of H2S. We and others have demonstrated that H2S increases eNOS phosphorylation on the stimulatory residue Ser1177, leading to eNOS activation and increased NO production. eNOS activation along with the indirect and direct anti-oxidant properties of H2S, facilitate the formation of increased amounts of cGMP. In addition, H2S exhibits phosphodiesterase inhibitory activity leading to a further increase in cGMP levels. Thus, some of the actions of H2S in the both the blood vessels and the heart are abolished by eNOS or cGMP-dependent protein kinase inhibition. During this presentation the cross-talk between H2S and NO in the context of vasorelaxation, angiogenesis and ischemia-reperfusion injury in the heart will be reviewed.