Since the discovery of nerve growth factor (NGF) in the 1950s and brain-derived neurotrophic factor (BDNF) in the 1980s, a great deal of evidence has mounted for the roles of neurotrophins (NGF; BDNF; neurotrophin-3, NT-3; and neurotrophin-4/5, NT-4/5) in development, physiology, and pathology. BDNF in particular has important roles in neural development and cell survival, as well as appearing essential to molecular mechanisms of synaptic plasticity and larger scale structural rearrangements of axons and dendrites. Basic activity-related changes in the central nervous system (CNS) are thought to depend on BDNF modulation of synaptic transmission. Pathologic levels of BDNF-dependent synaptic plasticity may contribute to conditions such as epilepsy and chronic pain sensitization, whereas application of the trophic properties of BDNF may lead to novel therapeutic options in neurodegenerative diseases and perhaps even in neuropsychiatric disorders. In this chapter, I review neurotrophin structure, signal transduction mechanisms, localization and regulation within the nervous system, and various potential roles in disease. Modulation of neurotrophin action holds significant potential for novel therapies for a variety of neurological and psychiatric disorders.