Trisomy 21 or Down syndrome (DS) is a complex syndrome, of genetic origin with multiple and variable neurobiological and neuropsychological manifestations. DS patients have consistent signs of brain damage along their lives, but understanding the biology of DS is complicated due to the extraordinary heterogeneity of the phenotypic signs. Thus, treatment of DS mental retardation poses significant challenges for clinicians and scientists. The review addresses the classical pharmacological and environmental treatments and also critically reviews the new possibilities that are emerging from the exciting advances in gene or cell therapy. We describe some of the most recent developments in the field and give a sense of the prospects for future prevention and therapy.