Signal transduction from nitric oxide (NO) is important in physiological processes such as smooth muscle relaxation and neurotransmission. NO signaling occurs through a variety of mechanisms, including S-nitrosylation (SNO) of sulfhydryl groups in protein. A paper in this issue of the journal dissects the regulatory system involved in SNO of caspase-3 and highlights the need for more direct investigations of the complex biological regulation by NO signaling.