Motor neuron disease (MND) is a devastating neurodegenerative condition associated with considerable disability and a poor prognosis. Despite improvements in symptomatic management in recent years, few therapies are available which modify survival. However, the challenge to find successful treatments would be greatly assisted by clearer elucidation of the underlying pathoaetiology. Many potential exogenous risk factors have been proposed as part of a gene-environment interaction in the aetiology of MND. A growing interest in the role of vigorous physical activity in the development of MND has followed reports of a higher than expected incidence of the disease in professional sports people. Such an association is also supported by current hypotheses concerning the cellular and genetic mechanisms of MND. However, evidence from epidemiological research remains conflicting and inconclusive. This article reviews the existing literature regarding physical activity as a risk factor for MND and the potential biological and genetic plausibility for this association.