Nicotinamide adenine dinucleotide (NAD+) is a critical cofactor essential for various cellular processes. Abnormalities in NAD+metabolism have also been associated with a number of metabolic disorders. The regulation and interconnection of NAD+metabolic pathways are not yet completely understood. By employing an NAD+intermediate-specific genetic system established in the model organismS. cerevisiae, we show that histone deacetylases (HDACs) Hst1 and Rpd3 link the regulation of the de novo NAD+metabolism-mediatingBNAgenes with certain aspects of the phosphate (Pi)-sensingPHOpathway. Our genetic and gene expression studies suggest that the Bas1–Pho2 and Pho2–Pho4 transcription activator complexes play a role in this co-regulation. Our results suggest a model in which competition for Pho2 usage between theBNA-activating Bas1–Pho2 complex and thePHO-activating Pho2–Pho4 complex helps balance de novo activity withPHOactivity in response to NAD+or phosphate depletion. Interestingly, both the Bas1–Pho2 and Pho2–Pho4 complexes appear to also regulate the expression of the salvage-mediatingPNC1gene negatively. These results suggest a mechanism for the inverse regulation between the NAD+salvage pathways and the de novo pathway observed in our genetic models. Our findings help provide a molecular basis for the complex interplay of two different aspects of cellular metabolism.