Mental retardation (MR) is one of the most common and severe developmental neurological syndromes. MR is typically described as a relatively non-progressive primary impairment of cognitive function and adaptive behavior. Its definition depends on whether medical, educational, legal, or other aspects are emphasized. Although environmental factors appear to play an important role in the etiology of MR in mildly affected individuals, it is unquestionable that even these exogenous agents act through disturbances in genetic developmental programs. The focus of this chapter is the neurobiology of MR; clinical and neurobiological evidence has suggested considerable overlap between the presentations of MR and autistic spectrum disorders. Consequently, some of the principles and features described in the chapter could be applicable to individuals with autism spectrum disorders. The extent to which presynaptic abnormalities are also present in MR have to be better characterized; the current emphasis on dendritic pathology is in part the consequence of methodological advantages of studying postsynaptic elements. Although knowledge of synaptic anomalies has led to novel pharmacological strategies, there is the possibility of using neurobiological information to plan more effective non-pharmacological interventions. © 2007 Elsevier Inc. All rights reserved.