Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with a fatal outcome. This review aims to report key epidemiological features of ALS in relation to the hypothesis of variation between populations, to summarize environmental hypothesis and to highlight current issues that deserve much considerations. Epidemiological ALS studies have shown a variation of incidence, mortality and prevalence between geographical areas and different populations. These data could support the notion that genetic factors, especially populations’ ancestries, along with environmental and lifestyle factors, play a significant role in the occurrence of the disease. To date, there is no strong evidence to confirm an association between a particular environmental factor and ALS. Physical activity (PA) has been extensively evaluated. Recent studies support with the best evidence level that PA in general population is not a risk factor for ALS. However, further research is needed to clarify the association of PA in some occupations and some athletic activities. Epidemiological research based on multicenter international collaboration is essential to provide new data on ALS especially in some regions of the world that are to date poorly represented in the ALS literature.