| Summary: | Beyond their established role as oxygen carriers, red blood cells have recently been found to contribute to systemic NO and sulfide metabolism and act as potent circulating antioxidant cells. Emerging evidence indicates that reactive species derived from the metabolism of O<sub>2</sub>, NO, and H<sub>2</sub>S can interact with each other, potentially influencing common biological targets. These interactions have been encompassed in the concept of the <i>reactive species interactome.</i> This review explores the potential application of the concept of <i>reactive species interactome</i> to understand the redox physiology of RBCs. It specifically examines how <i>reactive species</i> are generated and detoxified, their interactions with each other, and their targets. Hemoglobin is a key player in the <i>reactive species interactome</i> within RBCs, given its abundance and fundamental role in O<sub>2</sub>/CO<sub>2</sub> exchange, NO transport/metabolism, and sulfur species binding/production. Future research should focus on understanding how modulation of the <i>reactive species interactome</i> may regulate RBC biology, physiology, and their systemic effects.
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