Mental Retardation (MR) is a cognitive impairment affecting 3% of global population, characterised by subnormal intellectual functioning and impaired behavior. A large percent of individuals with mental deficiency have a significant chromosomal abnormality. Of these, Down syndrome (DS) is the major genetic cause of MR and contributes to about 30% of all moderate-to-severe cases of MR. This invalidating aspect of DS has hard impacts in public health and poses significant challenges for clinicians and scientists. Drug treatment identifications for MR in DS need understanding of the molecular mechanisms underlying this cognitive phenotype. In this golden period for DS research, with the development of animal and molecular models, and new techniques for transcriptional regulation, we could hope to rescue the basic molecular defects giving rise to MR.