Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of the motor neurons in the spinal cord, brainstem, and motor cortex. Ten percent of ALS cases are familial, with both autosomal dominant and recessive modes of inheritance reported. Mutations in the copper/zinc superoxidedismutase- 1 (SOD-1) gene, the first gene linked with ALS, result in the classical ALS phenotype. To date, 135 mutations have been identified in the SOD-1 gene, accounting for ∼ 20% of familial ALS cases. Mutations are widely distributed throughout the gene with preponderance for exon 4 and 5. Although mutations result in a toxic gain of function of the SOD-1 enzyme, which normally functions as a free radical scavenger, the mechanisms underlying motor neuron degeneration have not been clearly elucidated. Evidence is emerging of a complex interaction between genetic and molecular factors, with resultant damage of critical target proteins and organelles within the motor neuron. The clinical effectiveness afforded by anti-glutamatergic agents such as riluzole, suggests that glutamate excitotoxicity contributes to neurodegeneration in ALS, with glutamate excitotoxicity mediated via corticomotoneurons that provide a direct link between the motor cortex and the spinal motor neuron. This review provides an overview of the genetics of ALS, and describes recent advances in the understanding of the pathophysiological mechanisms underlying neurodegeneration.