The world population is growing older and age-related cognitive decline is becoming a burden of societal importance. D-serine is an endogenous amino acid that activates the co-agonist site of the NMDA-glutamate receptor, which is related to cognitive functions, such as learning and memory. Studies in aged rodents have shown a marked decrease in the levels of D-serine in brain regions such as the hippocampus, a key region for encoding memory. Exogenous administration of D-serine in rodents has demonstrated pro-cognitive effects in several brain functions, including memory and executive function. Further to animal studies, our group has observed an agerelated decrease in D-serine in the blood of healthy adults and elderly. The oral administration of D-serine induced significant improvement in executive function and spatial problem solving in elderly, some of the key cognitive domains affected by aging. In this review we propose the activation of the co-agonist site of NMDA receptors as a target to remediate features of the age-related cognitive decline. The cognitive effects of other agents targeting the co-agonist site of NMDA receptors are also discussed.