Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are a unique family of polypeptide growth factors that influence differentiation and survival of neurons in the developing nervous system. In adults, BDNF is important in regulating synaptic plasticity and connectivity in the brain. Recently, a common single-nucleotide polymorphism in the human BDNF gene, resulting in avaline to methionine substitution in the prodomain (Val66Met), has been shown to lead to memory impairment and susceptibility to neuropsychiatric disorders. An understanding of how this naturally occurring polymorphism affects behavior, anatomy, and cognition in adults is an important first step in linking genetic alterations in the neurotrophin system to definable biological outcomes in humans. We review the recent literature linking this BDNF polymorphism to cognitive impairment in the context of in vitro and transgenic animal studies that have established BDNF's central role in neuronal functioning in the adult brain.