Down syndrome (DS) is the most common genetically defined cause of intellectual disability and accounts for over 50% of the cases of Alzheimer-type dementia in persons younger than 50 years of age. At present, no pharmacotherapy aimed at counteracting either the neurodevelopmental or the neurodegenerative component of this genetic disorder has been approved. Recent preclinical and clinical work on the N-methyl-D-aspartate (NMDA) receptor antagonist memantine give us some reason for optimism, at least in relation to the potential for a partial pharmacological improvement of hippocampus dependent memory deficits associated with DS. Here, we will review briefly the roles of NMDA receptors in health and disease, including the glutamatergic hypothesis for Alzheimer disease. Then, we will describe the basis for a glutamatergic hypothesis for DS, by reviewing the available preclinical evidence and assessing potential molecular mechanisms for NMDA receptor dysfunction in DS. A short description of the first two clinical trials of memantine in young and older adults with DS will follow. We will conclude by reviewing three caregiver reports from our recent clinical study and some lessons we have learned designing and conducting the first translational study in the field of DS to arise directly from experimental results in animal models.