Abstract: Nicotinamide adenine dinucleotide (NAD) is one of the most important metabolites in mammalian cells (Figure 1A). Its oxidized form (NAD+) and reduced form (NADH) play a role in many reactions within cells, most prominently in the redox reactions that lead to the production of ATP. NAD functions more broadly than that, however, and is considered to be involved in hundreds of different biological events (Lautrup et al., 2019). Production of NAD+ in mammalian cells occurs mainly via the salvage pathway, which utilizes nicotinamide (NAM), a product of NAD+ degradation, to re-synthesize NAD+ (Figure 1B). This occurs in two steps (Garten et al., 2015): first, NAM and phosphoribosyl pyrophosphate are condensed to nicotinamide mononucleotide (NMN) by the enzyme nicotinamide phosphoribosyl transferase (NAMPT); second, NMN and ATP are used by nicotinamide mononucleotide adenylyltransferase 1–3 to produce NAD+. NAMPT functions as the rate-limiting enzyme of the NAD+ salvage pathway (Revollo et al., 2004). More recently, the therapeutic potential of NAD+ and NAD+ biosynthesis has been investigated, with focus on metabolic diseases, cancer, aging and neurodegeneration (Garten et al. 2015; Lautrup et al., 2019). The relationship between NAD+ and neurodegeneration has been actively investigated; however, less is understood concerning the impact of NAD+ and NAD+ biosynthesis on the neuromuscular junction (NMJ), the synapse where motor neurons interact with skeletal muscle, and how muscles and neurons respond to disruptions in NAD homeostasis. Our recent studies have demonstrated that NAMPT deletion in projection neurons significantly impacts the function of NMJs (Wang et al. 2017; Lundt et al. 2020), indicating a non-cell autonomous effect of neuronal NAMPT on NMJs. NMJs are significantly affected following the loss of NAMPT from projection neurons in mice with a phenotype similar to what is observed in motor neuron diseases, especially amyotrophic lateral sclerosis.