Autism spectrum disorders are neurodevelopmental disorders characterized by deficits in social skills, communication, and motor function, as well as compulsive and repetitive behaviors and interests. Although these disorders are thought to be of multifactorial origin, with a wide range of genetic and environmental factors implicated, we propose that excitoxicity is the mechanism modulating numerous risk factors. Substantial evidence from a number of sources—including laboratory studies, neuroimaging, postmortem data, and genetic studies—supports a role for excitotoxicity in autism spectrum disorders. These studies often implicate glutamate and glutamatergic dysregulation as the key mechanism driving excitotoxic processes. The relationship of autism spectrum disorders to other diseases in which glutamate plays a critical role gives further support to the glutamatergic theory of autism. If glutamate contributes to the pathology of autism spectrum disorders, it is reasonable to suggest that agents modulating glutamate may have some utility in treatment. To this end, numerous reports have supported roles for medications including memantine, depakote, amantadine, and antipsychotics in the treatment of these disorders. Investigations thus far have consisted mainly of small open-label and uncontrolled studies; larger controlled studies are necessary and are underway.