The causes of amyotrophic lateral sclerosis (ALS) are poorly understood. A small proportion, about 2%, is associated with a mutation in the superoxide dismutase (SOD1) gene, and mice expressing this mutant gene exhibit a progressive, ALS-like neurodegenerative disease. Studies of these animals, as well as of human post mortem tissue, reveal the presence of multiple pathological processes, including oxidative stress, glutamate excitotoxicity, neuroinflammation, mitochondrial degeneration, alterations in neurofilaments and neurotubules, mitochondrial damage, aggregation of proteins, abnormalities in growth factors, and apoptosis. We propose that alterations in the disposition of zinc ions may be important in the initiation and development of ALS. SOD1 binds zinc, and many of the mutant forms of this enzyme associated with ALS show altered zinc binding. Alterations in the expression of metallothioneins (MTs), which regulate cellular levels of zinc, have been reported in mutant SOD1 mice, and deletion of MTs in these animals accelerates disease progression. Zinc plays a key role in all the pathological processes associated with ALS. Our zinc hypothesis also may help explain evidence for environmental factors in some cases of ALS, such as in the Chamorro tribe in Guam and in the Gulf War.