NAD⁺ has emerged as a vital cofactor that can rewire metabolism, activate sirtuins, and maintain mitochondrial fitness through mechanisms such as the mitochondrial unfolded protein response. This improved understanding of NAD⁺ metabolism revived interest in NAD⁺-boosting strategies to manage a wide spectrum of diseases, ranging from diabetes to cancer. In this review, we summarize how NAD⁺ metabolism links energy status with adaptive cellular and organismal responses and how this knowledge can be therapeutically exploited.