Due to the prevalence of neuromuscular disorders such as amyotrophic lateral sclerosis and spinal muscular atrophy in modern societies, defining new and efficient strategies for the treatment of these two neurodegenerative diseases has become a vital and still unfulfilled urge. Several lines of experimental evidence have emphasized the benefits of regular exercise training in mouse models for these affections in terms of life span increase and improvement of both motor capacities and motoneuron survival. Identifying molecules that could mimic the neuroprotective effects of exercise represents a promising way to find novel therapies. Some of the effects of exercise are caused by the overproduction of circulating neurotrophic factors, such as IGF-I, whereas others may be due to modifications of the intrinsic properties of the motoneurons within the spinal cord. The causal relationship that links these potential effects of exercise training and the improvement of motor capacity and life span expectancy is consequently discussed.