Neurotrophins are critical to the development and maintenance of the mammalian central nervous system. Among them is brain‐derived neurotrophic factor (BDNF), whose synthesis and release is targeted by activation of glutamate receptors. Perturbation of this process probably underlies neurodegenerative and psychiatric disorders. A naturally occurring variation in humans, in the form of a common single‐nucleotide polymorphism in the pro region of the polypeptide at codon 66 (Val66→Met), affects processing of the pro‐BDNF polypeptide and its activation‐dependent release. This variant is associated with differences in the volume of the hippocampal formation and with anxiety and depression‐related phenotypes. Convergent findings supporting a role for BDNF in alterations to hippocampal structure and behavior are found in a “humanized” BDNF transgenic mouse. Also, recent human genetic studies have supported a role of BDNF signaling in addictive behaviors by allele‐, genotype‐, and haplotype‐based association of the TrkB gene, which encodes the cognate receptor for BDNF, with alcohol dependence. A better understanding of the influence of BDNF‐mediated pathways in cell survival and plasticity will aid in developing new approaches to restoring normal function in disease states.