Amyotrophic lateral sclerosis (ALS) is a multifactorial disease in which oxidative stress, mitochondrial damage, excitotoxicity, protein aggregation and impairment of axonal transport are involved, and a multisystem disease, where damage in motor neurons in the ventral horn of the spinal cord is intertwined with damage to non-neuronal cells. Our knowledge of the molecular mechanisms operating in ALS has greatly benefited from studies on models based on the expression of mutant SOD1s found in patients. However, what happens to the great majority of patients, who do not carry mutSOD1, is not clear. Overall, available evidence suggests that mechanisms that affect cellular redox stress either directly through mitochondrial alterations or indirectly may provide a unifying explanation for the pathogenesis of this disease.