Skeletal muscle is a tissue integral to general health. Due to its high abundance and oxidative capacity, its metabolism is intimately linked to whole-body physiology. In the elderly population, mobility correlates positively with life expectancy and survival. Furthermore, regular physical activity is one of the most effective health-promoting interventions that delay the onset of aging-associated chronic diseases. Data from preclinical studies show that aging of various tissues is accompanied by a decrease in the concentration of nicotinamide adenine dinucleotide (NAD), which plays a central role in energy homeostasis. Thus, a hypothesis has emerged that normalization of its content would ameliorate the age-related decline in tissue function and therefore improve health of the elderly. This idea, along with the documented safety and high tolerability of NAD precursor supplementation, makes NAD metabolism a prospective target for anti-aging interventions. Interestingly, muscle NAD biosynthesis pathways are stimulated by exercise training, which suggests that training-induced adaptations rely on tissue NAD levels. However, while the relationship between muscle fitness and regular physical activity is well-characterized, the proposed synergy between muscle NAD replenishment and exercise training has not been established. Here, we review the published data on the role of NAD metabolism in exercise in the context of young and aged skeletal muscle and discuss the current challenges relevant to the field.