Abstract: Motor neurons are highly polarized cells, with long axons that extend to more than 1 m in the adult human. The axons further arborize into a specialized synaptic compartment, the motor unit, containing up to 2000 neuromuscular junctions (NMJs). While the size of other neuronal synapses can be up to 1 µm, the NMJ is much larger and can reach 10–30 µm (Jones et al., 2017). The vast size of the motor unit requires motor neurons to evolutionally adapt and supply this distal portion with a sufficient amount of ATP, as well as to replenish the axonal protein pool in order to maintain their synapses. To address its substantial energetic needs, the NMJ is enriched with a vast network of mitochondria. This is supported by ultrastructural studies using electron and confocal microscopy, which revealed that only ~50% of active synapses in the adult rodent central nervous system (CNS) contain any mitochondria, whereas all NMJs are enriched with a tightly packed mitochondrial network (Misgeld and Schwarz, 2017; Altman et al., 2019). The mechanisms leading to this distinct enrichment, as well as its implications and functional meaning in the context of neurodegeneration, remain poorly understood. Here, we discuss and suggest a possible explanation for how the mitochondrial enrichment of the NMJ can be relevant to the selective vulnerability of motor neurons in motor neuron diseases, and in particular amyotrophic lateral sclerosis (ALS).