S-Nitrosothiols (RSNOs) have been used widely as experimental nitric oxide (NO) donors, but the clinical use of these agents remains limited. Recent data support a role for endogenous RSNOs as mediators of NO signaling via the post-translational modification of proteins. This review discusses the increased understanding of the role of RSNOs in NO signaling, as well as emerging insights into NO donor-dependent and -independent mechanisms of action of RSNOs, in the context of emerging and potential therapeutics that target endogenous RSNOs or use synthetic RSNOs to stimulate NO signaling. The focus of this review is the treatment of diabetes and metabolic disease, pathologies in which dysfunction in NO signaling is clearly implicated.