Aging is associated with gradual degeneration, in mass and function, of the neuromuscular system. This process, referred to as “sarcopenia”, is considered a disease by itself, and it has been linked to a number of other serious maladies such as type II diabetes, osteoporosis, arthritis, cardiovascular disease, and even dementia. While the molecular causes of sarcopenia remain to be fully elucidated, recent findings have implicated the neuromuscular junction (NMJ) as being an important locus in the development and progression of that malady. This synapse, which connects motor neurons to the muscle fibers that they innervate, has been found to degenerate with age, contributing both to senescent-related declines in muscle mass and function. The NMJ also shows plasticity in response to a number of neuromuscular diseases such as amyotrophic lateral sclerosis (ALS) and Lambert-Eaton myasthenic syndrome (LEMS). Here, the structural and functional degradation of the NMJ associated with aging and disease is described, along with the measures that might be taken to effectively mitigate, if not fully prevent, that degeneration.