Drug addiction is a common psychiatric disorder with complex genetic, psychological and social contributing factors. While the midbrain dopaminergic system is crucial for acute reward and the initiation of addiction, evidence suggests that there are permanent neuronal changes at the cellular and molecular levels that underlie the addictive process. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family and the most abundant neurotrophins in the brain, plays a key role in the survival and differentiation of midbrain dopaminergic (DA) neurons. Evidence from animal and clinical studies suggests that increased central BDNF activity may be implicated in the pathogenesis of drug addiction. For example, BDNF infusion into rat midbrain enhances the rewarding effects of cocaine as measured by the condition place preference paradigm. In contrast, cocaine-conditioned place preference was reduced in heterozygous BDNF knockout mice. In humans, the 66Val allele of the BDNF-gene Val66Met polymorphism is associated with higher BDNF secretion in response to neuronal stimulation compared with the 66Met allele. We found higher BDNF 66Val homozygote frequency in people with drug addiction compared with normal controls. Furthermore, plasma BDNF concentrations of methamphetamine users were significantly higher than controls. The increased central BDNF activity hypothesis of drug addiction may provide new insights for improved therapeutic strategies for the prevention and treatment of drug addiction. Several strategies to decrease central BDNF activity that have potential use in the treatment of drug addiction are proposed.