Amyotrophic lateral sclerosis (ALS) is one of the major forms of motor neuron disease (MND), a group of degenerative disorders causing progressive motor neuron death leading to eventual paralysis and death. The pathogenesis of MND is poorly understood and may include genetic and/or environmental factors, with a common end-stage outcome. The majority of cases are sporadic, with a small percentage of familial cases identified. Mutations in the copper/zinc superoxide dismutase (SOD1) enzyme are frequent in familial ALS, and have allowed for the development of transgenic SOD1 rodent models of ALS. There has been evidence for immune system involvement in the disease, and activated components of the classical complement pathway have been observed in the serum, cerebrospinal fluid and neuronal tissue of diseased individuals. Furthermore, motor neurons and spinal cord tissue from SOD1 transgenic mice show an upregulation in C1q mRNA transcript and protein, in some cases prior to disease onset. Our laboratory has preliminary data indicating a specific pathogenic role for the activation fragment of complement C5 (C5a) in this disease. Using selective C5a receptor antagonists, we dosed SOD1 transgenic rats and observed an extension in survival and reduced motor symptoms compared to untreated rats. Collectively, these clinical and experimental findings suggest that targeting complement using specific inhibitors may represent a novel therapeutic approach to treating MND. Further experimental and clinical studies are required to validate this hypothesis. This review will summarize the clinical and experimental evidence to date implicating complement in the pathogenesis of MND.