The study investigates the circadian control of the NAD+ salvage pathway by CLOCK and SIRT1. It demonstrates that intracellular NAD+ levels oscillate with a 24-hour rhythm, driven by the circadian clock. CLOCK:BMAL1 regulates the expression of NAMPT, a key enzyme in the NAD+ salvage pathway, which is essential for NAD+ synthesis. SIRT1, a NAD+-dependent histone deacetylase, is recruited to the Namp1 promoter and contributes to the circadian synthesis of its own coenzyme. Using the NAMPT inhibitor FK866, the authors show that NAMPT is crucial for modulating circadian gene expression. The findings reveal an interlocked transcriptional-enzymatic feedback loop that governs the molecular interplay between cellular metabolism and circadian rhythms, highlighting the importance of NAD+ oscillation in regulating metabolic tissues and peripheral clocks.The study investigates the circadian control of the NAD+ salvage pathway by CLOCK and SIRT1. It demonstrates that intracellular NAD+ levels oscillate with a 24-hour rhythm, driven by the circadian clock. CLOCK:BMAL1 regulates the expression of NAMPT, a key enzyme in the NAD+ salvage pathway, which is essential for NAD+ synthesis. SIRT1, a NAD+-dependent histone deacetylase, is recruited to the Namp1 promoter and contributes to the circadian synthesis of its own coenzyme. Using the NAMPT inhibitor FK866, the authors show that NAMPT is crucial for modulating circadian gene expression. The findings reveal an interlocked transcriptional-enzymatic feedback loop that governs the molecular interplay between cellular metabolism and circadian rhythms, highlighting the importance of NAD+ oscillation in regulating metabolic tissues and peripheral clocks.