Drugs of abuse produce widespread effects on the structure and function of neurons throughout the brain's reward circuitry, and these changes are believed to underlie the long-lasting behavioral phenotypes that characterize addiction. Although the intracellular mechanisms regulating the structural plasticity of neurons are not fully understood, accumulating evidence suggests an essential role for neurotrophic factor signaling in the neuronal remodeling which occurs after chronic drug administration. Brain-derived neurotrophic factor (BDNF), a growth factor enriched in brain and highly regulated by several drugs of abuse, regulates the phosphatidylinositol 3'-kinase (PI3K), mitogen-activated protein kinase (MAPK), phospholipase Cgamma (PLCgamma), and nuclear factor kappa B (NFkappaB) signaling pathways, which influence a range of cellular functions including neuronal survival, growth, differentiation, and structure. This review discusses recent advances in our understanding of how BDNF and its signaling pathways regulate structural and behavioral plasticity in the context of drug addiction.