Down syndrome (DS) is a genetic pathology caused by the triplication of human chromosome 21. Although individuals with DS have various medical problems, intellectual disability is the most invalidating aspect of the pathology. Despite numerous efforts, the mechanisms whereby gene triplication leads to the DS phenotype have not been elucidated and there are, at present, no therapies to rescue brain developmental alterations and mental disability in individuals with DS. In this review, we focused on the major defects of the DS brain, comparing data regarding humans with DS and mouse models for DS, and therapeutic interventions attempted on animal DS models. Based on the promising results of pharmacotherapies in these models, we believe that it is possible to conclude that tools to improve brain development in DS are now almost at hand. We now know that it is possible to rescue and/or improve neurogenesis, neuron maturation, connectivity, neurodegeneration and behavior. We believe that the knowledge gained in DS mouse models provides a rational basis to start new clinical trials in infants, children and adults with DS, exploiting drugs that have proved able to rescue various facets of the DS neurologic phenotype. It is not unreasonable to consider that the results of these trials may provide a positive answer to the question: 'Is it possible to improve brain development in DS?'.