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Nicotinamide adenine dinucleotide (NAD⁺) is an essential metabolite involved in various cellular processes. The cellular NAD⁺ pool is maintained by three biosynthesis pathways, which are largely conserved from bacteria to human. NAD⁺ metabolism is an emerging therapeutic target for several human disorders including diabetes, cancer, and neuron degeneration. Factors regulating NAD⁺ homeostasis have remained incompletely understood due to the dynamic nature and complexity of NAD⁺ metabolism. Recent studies using the genetically tractable budding yeast <i>Saccharomyces cerevisiae</i> have identified novel NAD⁺ homeostasis factors. These findings help provide a molecular basis for how may NAD⁺ and NAD⁺ homeostasis factors contribute to the maintenance and regulation of cellular function. Here we summarize major NAD⁺ biosynthesis pathways, selected cellular processes that closely connect with and contribute to NAD⁺ homeostasis, and regulation of NAD⁺ metabolism by nutrient-sensing signaling pathways. We also extend the discussions to include possible implications of NAD⁺ homeostasis factors in human disorders. Understanding the cross-regulation and interconnections of NAD⁺ precursors and associated cellular pathways will help elucidate the mechanisms of the complex regulation of NAD⁺ homeostasis. These studies may also contribute to the development of effective NAD⁺-based therapeutic strategies specific for different types of NAD⁺ deficiency related disorders.