The circadian clock regulates the NAD⁺ salvage pathway through the enzyme NAMPT, which is controlled by the CLOCK:BMAL1 complex. NAD⁺ levels oscillate with a 24-hour rhythm, driven by the circadian clock. CLOCK:BMAL1 regulate the circadian expression of NAMPT, a key enzyme in the NAD⁺ salvage pathway. SIRT1, a NAD⁺-dependent deacetylase, is recruited to the NAMPT promoter and contributes to the circadian synthesis of its own coenzyme. The NAD⁺ salvage pathway is essential for maintaining circadian rhythms, as evidenced by the circadian oscillation of NAD⁺ and NAM levels in wild-type mouse embryo fibroblasts (MEFs). In contrast, NAD⁺ and NAM levels do not oscillate in MEFs from clock mutant or arrhythmic mice, indicating that the circadian clock controls these metabolites. The study also shows that NAMPT is required for circadian gene expression, as demonstrated by the use of the specific inhibitor FK866, which lowers NAD⁺ and NAM levels and disrupts circadian gene expression. The findings reveal an interlocked transcriptional-enzymatic feedback loop that governs the molecular interplay between cellular metabolism and circadian rhythms. The circadian clock controls the levels of NAD⁺ and NAM through the NAMPT enzyme, which is regulated by CLOCK:BMAL1. This feedback loop is essential for maintaining circadian rhythms and may have implications for diseases involving deregulated apoptosis or genotoxic stress. The study highlights the importance of the NAD⁺ salvage pathway in circadian regulation and suggests that targeting NAMPT could be a potential therapeutic approach.The circadian clock regulates the NAD⁺ salvage pathway through the enzyme NAMPT, which is controlled by the CLOCK:BMAL1 complex. NAD⁺ levels oscillate with a 24-hour rhythm, driven by the circadian clock. CLOCK:BMAL1 regulate the circadian expression of NAMPT, a key enzyme in the NAD⁺ salvage pathway. SIRT1, a NAD⁺-dependent deacetylase, is recruited to the NAMPT promoter and contributes to the circadian synthesis of its own coenzyme. The NAD⁺ salvage pathway is essential for maintaining circadian rhythms, as evidenced by the circadian oscillation of NAD⁺ and NAM levels in wild-type mouse embryo fibroblasts (MEFs). In contrast, NAD⁺ and NAM levels do not oscillate in MEFs from clock mutant or arrhythmic mice, indicating that the circadian clock controls these metabolites. The study also shows that NAMPT is required for circadian gene expression, as demonstrated by the use of the specific inhibitor FK866, which lowers NAD⁺ and NAM levels and disrupts circadian gene expression. The findings reveal an interlocked transcriptional-enzymatic feedback loop that governs the molecular interplay between cellular metabolism and circadian rhythms. The circadian clock controls the levels of NAD⁺ and NAM through the NAMPT enzyme, which is regulated by CLOCK:BMAL1. This feedback loop is essential for maintaining circadian rhythms and may have implications for diseases involving deregulated apoptosis or genotoxic stress. The study highlights the importance of the NAD⁺ salvage pathway in circadian regulation and suggests that targeting NAMPT could be a potential therapeutic approach.