Nicotinamide adenine dinucleotide (NAD+) is a critical metabolite that acts as a cofactor in energy metabolism, and serves as a cosubstrate for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+metabolism can regulate functionality attributes of innate and adaptive immune cells and contribute to inflammatory responses. Thus, the manipulation of NAD+bioavailability can reshape the courses of immunological diseases. Here, we review the basics of NAD+biochemistry and its roles in the immune response, and discuss current challenges and the future translational potential of NAD+research in the development of therapeutics for inflammatory diseases, such as COVID-19.