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Activation and subsequent differentiation of T cells following antigenic stimulation are triggered by highly coordinated signaling events that lead to instilling cells with a discrete metabolic and transcriptional feature. Compelling studies indicate that intracellular nicotinamide adenine dinucleotide (NAD⁺) levels have profound influence on diverse signaling and metabolic pathways of T cells, and hence dictate their functional fate. CD38, a major mammalian NAD⁺ glycohydrolase (NADase), expresses on T cells following activation and appears to be an essential modulator of intracellular NAD⁺ levels. The enzymatic activity of CD38 in the process of generating the second messenger cADPR utilizes intracellular NAD^+, and thus limits its availability to different NAD⁺ consuming enzymes (PARP, ART, and sirtuins) inside the cells. The present review discusses how the CD38-NAD⁺ axis affects T cell activation and differentiation through interfering with their signaling and metabolic processes. We also describe the pivotal role of the CD38-NAD⁺ axis in influencing the chromatin remodeling and rewiring T cell response. Overall, this review emphasizes the crucial contribution of the CD38⁻NAD⁺ axis in altering T cell response in various pathophysiological conditions.