Nitric oxide (NO·) signaling is diverse, and involves reaction with free radicals, metalloproteins, and specific protein amino acid residues. Prominent among these interactions are the heme protein soluble guanylate cyclase and cysteine residues within several proteins such as caspases, the executors of apoptosis. Another well characterized site of NO· binding is the terminal complex of the mitochondrial respiratory chain, cytochrome c oxidase, although the downstream signaling effects of this interaction remain unclear. Recently, it has been recognized that the intracellular formation of hydrogen peroxide (H2O2) by controlled mechanisms contributes to what we term "redox tone," and so controls the activity and activation thresholds of redox-sensitive signaling pathways. In this hypothesis paper, it is proposed that NO·-dependent modulation of the respiratory chain can control the mitochondrial generation of H2O2 for cell signaling purposes without affecting ATP synthesis. © 2002 Elsevier Science Inc.