Over the past decade, hydrogen sulfide has emerged as an important cardioprotective molecule with potential for clinical applications. Although several pathways have been proposed to mediate the beneficial effects of H2S, the NO/cGMP axis has attracted significant attention. Recent evidence has suggested that cGMP-dependent protein kinase can lie both downstream and upstream of H2S. The current literature on this topic is reviewed and data from recent studies are integrated to propose a unifying model.