NAD+ is a crucial molecule controlling various metabolic processes. It serves as a coenzyme for several dehydrogenases in redox reactions and a substrate for enzymes consuming NAD+, including NAD glycohydrolases (CD38, CD157, and SARM1), deacetylases (SIRT), and mono- or poly-ADP-ribose transferases (ARTs and PARPs) (Sharif et al., Antioxid Redox Signal. 30:906–923, 2019; Gossmann et al., FEBS J. 279:3355–63, 2012). Many studies have revealed that some of these enzymes involved in NAD+ synthesis and metabolism exhibit immune regulatory properties, playing vital roles in various biological processes, such as aging, tumorigenesis, and immune cell metabolic reprogramming, among others. Of particular interest, some scientists propose that cellular levels of NAD+ could regulate the immune response to COVID-19, suggesting NAD+ is a potential immunomodulator for improving clinical symptoms in patients (Zheng et al., Trends Immunol. 43:283–295, 2022). This chapter will focus on elucidating the important roles of NAD+ and NAD+ synthesis metabolic enzymes in several immunological processes and their potential applications.