Physical exercise exerts a wide range of benefits on an organism's overall health and well-being. Exercise contributes positively toward an individual's healthy weight, muscle strength, immune system, and cardiovascular health. Indeed, exercise has been demonstrated to reduce life-threatening conditions such as high blood pressure, heart disease, obesity, and diabetes. Of particular interest to this review, exercise has also been shown to be neuroprotective in both the central and peripheral nervous systems. Naturally, such findings apply broadly to the study of neurodegenerative disease with numerous reports demonstrating that exercise has beneficial effects on disease progression. One of the most devastating neurodegenerative diseases is amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease in the United States, or motor neuron disease in the United Kingdom, resulting from the progressive loss of brain and spinal cord motor neurons. Several human studies show that moderate exercise regimens improve ALS patients' scoring on functionality tests and ameliorate disease symptoms. Other promising recent works using transgenic mouse models of familial ALS have shown markedly slowed disease progression, improved function, and extension of survival in moderately exercised animals. Possible explanations for these findings include the exercise-induced changes in motor neuron morphology, muscle-nerve interaction, glial activation, and altering levels of gene expression of anti-apoptotic proteins and neurotrophic factors in the active tissue. Here we review the current literature on exercise and motor neuron disease, focusing on rodent and human studies to define the proper type, intensity, and duration of exercise necessary to enhance neuron survival as well discuss current mechanistic studies to further define the exercise-mediated pathways of neuroprotection.