Trisomy 21 (T21) is the most common autosomal aneuploidy that is associated with intellectual disability. It is the focus of many prenatal screening programs across the globe. Pregnant women who receive a prenatal diagnosis of T21 in their fetus currently have the option of continuing or terminating their pregnancy, but no fetal treatment is available. In this paper, we review compelling morphogenetic, cellular, and molecular studies that, taken together, suggest that there is an important window of opportunity during fetal life to positively impact brain development to improve postnatal neurocognition and behavior. Although substantial progress has been made in understanding the basic neurobiology of Down syndrome (DS), the majority of pre-clinical trials is currently focused on adults. There are a number of challenges in the identification and development of novel antenatal therapies for DS, including the lack of toxicity and teratogenicity for the pregnant woman and the fetus, evidence that the compounds can cross the placenta and achieve therapeutic levels, and the demonstration of clinical improvement. Preliminary experiments in mouse models suggest that prenatal treatment of DS is an achievable goal. © 2013 John Wiley & Sons, Ltd.