This paper describes recent advances in the neurobiology of mental retardation, emphasizing new diagnostic resources provided by cytogenetics, molecular testing, and neuroimaging.MEDLINE (January 2000 through October 2003), using the following key words: mental retardation, developmental disability, child, and adolescent. Search of the Pediatrics and New England Journal of Medicine websites using the key word mental retardation. The Online Mendelian Inheritance in Man (OMIM) database was searched for information on clinical genetics.In October 2003, the number of genetic syndromes associated with mental retardation reached 1,149. Considering the genetic or environmental and congenital or acquired causes of mental retardation, current diagnostic investigation is able to detect the etiology in 50 to 70% of cases.Diagnostic evaluation should follow a stepwise approach in order to make rational use of the expensive tools of cytogenetics, molecular biology, and neuroimaging.