Key points emerging from this review include: (i) the balance of evidence over the past 13 years favours the conclusion that participation in frequent and strenuous leisure-time PA is a risk factor for the development of ALS; (ii) specific genetic backgrounds predisposing to exercise-induced ALS are being identified with early data highlighting the interaction with C9orf72 mutations; (iii) specific strenuous PAs that have been studied in the context of ALS include soccer, American football and long-distance skiing. This evidence concerns the gene C9orf72 and amyotrophic lateral sclerosis.