Mesenchymal stem/stromal cells (MSCs) possess robust immunoregulatory functions and are promising therapeutics for inflammatory disorders. This capacity is not innate but is activated or ‘licensed’ by inflammatory cytokines. The licensing mechanism remains unclear. Here, we examined whether inflammatory cytokines metabolically reprogrammed MSCs to confer this immunoregulatory capacity...When NAD+ synthesis was blocked by inhibiting or depleting NAMPT, the immunosuppressive function of MSCs induced by inflammatory cytokines was greatly attenuated. Consequently, when NAD+ metabolism in MSCs was perturbed, their therapeutic benefit was decreased in mice suffering from inflammatory bowel disease and acute liver injury. Further analysis revealed that NAMPT-driven production of NAD+ was critical for the inflammatory cytokine-induced increase in glycolysis in MSC..This study demonstrated that unlike its proinflammatory role in immune cells, NAD+ metabolism governs the anti-inflammatory function of MSCs during inflammation.