Motor neuron disease refers to a spectrum of disorders resulting from degeneration of the upper or lower motor neurons or both. Amyotrophic lateral sclerosis is the most common form of motor neuron disease, in which patients demonstrate evidence of both anterior horn cell (lower motor neuron) and corticospinal tract (upper motor neuron) dysfunction. Several theories regarding the pathogenesis of amyotrophic lateral sclerosis have emerged, including glutamate excitotoxicity, free radical oxidative stress, cytoskeletal abnormalities, a deficiency of neurotrophic factor, autoimmunity, apoptosis, and viral infection. Numerous clinical trials have been completed based on these possible mechanisms of the disease propagation including treatment with antiglutamate agents, anti-oxidants, immunosuppressants, and neurotrophic factors. Several of these trials have shown modest effects in slowing the disease course. None, however, have yielded marked benefit in arresting disease progression. The most significant effect in abating disease progression has been our use and understanding of aggressive symptomatic therapy to reduce disability, enhance quality of life, and improve prognosis.