AbstractDue in part to the favorable demographics of Alzheimer's disease in the general population, pharmaceutical companies worldwide are aggressively pursuing the research and development of cognitive‐enhancing drugs. There have been two rather noteworthy successes in recent years as both tacrine and donepezil have received FDA approval as useful pharmacologic treatment for Alzheimer's disease. Given what is now known regarding the critical periods for synaptic development and the organization of large‐scale neuronal circuits in the developing cerebral cortex, it appears that there may exist a window of opportunity during which specifically targeted, pharmacologic intervention could exert a significantly favorable biologic effect during development. Pharmacologic agents that increase the brain's responsiveness to activity‐dependent plasticity may be of particular therapeutic benefit to children with some forms of mental retardation. Currently available medications designed for use in adults with dementia have targeted cholinergic neurotransmission and to a lesser degree glutamatergic neurotransmission, both of which play important roles in learning, memory, and developmental organization of the brain. The “cholinergic hypothesis” of memory dysfunction has done much to focus research efforts on cholinergic strategies for the enhancement of learning and memory. Medications that affect cholinergic neurotransmission include acetylcholine precursors, acetylcholinesterase inhibitors, and muscarinic agonists. Drugs targeting the glutamatergic system are among the most novel modalities in treating disorders of memory and learning. These drugs have grown in proportion to advancements in our understanding of the physiologic and pathologic effects of this important excitatory amino acid neurotransmitter. The most important class of medications that affect glutamatergic neurotransmission include nootropics (ampakines) and glycinergic compounds. The rationale for using drugs that act on the glutamatergic system during critical periods for neuronal organization depends, in part, on the degree to which abnormal dendritic spine morphology and/or function associated with some forms of mental retardation is mediated by dysfunctional glutamatergic neurotransmission. It also depends to what degree spine morphology and/or function can be modified in these conditions. MRDD Research Reviews 1998;4:36–49. © 1998 Wil