Abstract: Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MNs). Although a small percentage of ALS has a familial origin, the vast majority of cases are sporadic in which genetic factors and environment interact with each other leading to disease onset in genetically predisposed individuals. In the current model of the disease, each individual has a determined genetic load, some degree of cell degeneration related to age and several risky environmental exposures. In this scenario, MN degeneration would occur when the sum of these factors reach a certain threshold. To date, an extensive list of environmental factors has been associated to ALS, including different categories, such as exposure to heavy metals and other toxicants, cyanotoxins or infectious agents. In addition, in recent years, lifestyle and other demographic parameters are gaining relevance in the genesis of the disease. Among them, physical activity, nutrition, body mass index, cardiovascular risk factors, autoimmune diseases and cancer are some of the conditions which have been related to the disease. In this review, we will discuss the potential mechanisms of environmental conditions in motor neuron degeneration. Understanding the role of each one of these factors as well as their interactions appears as a crucial step in order to develop new preventive, diagnostic and therapeutic approaches for ALS patients.

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