BDNF is synthesized and secreted by excitatory neurons. Decades of work with animal models prepared the ground for interpreting the results of human genome analyses associating polymorphisms with memory deficits, mood disorders and dysregulation of food intake. These association studies include a frequent human polymorphism causing an amino acid substitution in the protein coding sequence of BDNF. Even if its biochemical impact is still incompletely understood, this polymorphism helped understanding the role of BDNF in humans in specific aspects of memory, neurodegeneration and in CNS re-myelination after lesion. BDNF is stored with its pro-peptide in the presynaptic terminals of excitatory neurons. Both are released when neurons are activated by the pattern of stimuli that also efficiently increase the transcription of the BDNF gene. While the restricted availability is a key aspect of BDNF's physiology, this feature greatly complicated studies of its biochemistry and cell biology. It also led to the extensive use of overexpression paradigms that generated considerable confusion. As a result, the notion that BDNF is released from neurons after intracellular processing of its precursor is not universally shared, nor is its accumulation in pre-synaptic nerve terminals as opposed to dendrites. Beyond the use of drugs reported to activate the BDNF/TrkB pathway such as commonly used antidepressants, therapeutic successes have been limited thus far. However, as BDNF signaling is now better understood, rapid progress can now be expected. Meanwhile physical activity remains the most realistic option to maintain BDNF levels and delay cognitive decline during ageing.