Down syndrome, the most common genetic cause of intellectual disability, is associated with brain disorders due to chromosome 21 gene overdosage. Molecular and cellular mechanisms involved in the neuromorphological alterations and cognitive impairments are reported herein in a global model. Recent advances in Down syndrome research have lead to the identification of altered molecular pathways involved in intellectual disability, such as Calcineurin/NFATs pathways, that are of crucial importance in understanding the molecular basis of intellectual disability pathogenesis in this syndrome. Potential treatments in mouse models of Down syndrome, including antagonists of NMDA or GABA[subscript A] receptors, and microRNAs provide new avenues to develop treatments of intellectual disability. Nevertheless, understanding the links between molecular pathways and treatment strategies in human beings requires further research.