The proteins of the mammalian neurotrophin family (nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5)) were originally identified as neuronal survival factors. During the last decade, evidence has accumulated implicating them (especially BDNF) in addition in the regulation of synaptic transmission and synaptogenesis in the CNS. However, a detailed understanding of the secretion of neurotrophins from neurons is required to delineate their role in regulating synaptic function. Some crucial questions that need to be addressed include the sites of neurotrophin secretion (i.e. axonal versus dendritic; synaptic versus extrasynaptic) and the neuronal and synaptic activity patterns that trigger the release of neurotrophins. In this article, we review the current knowledge in the field of neurotrophin secretion, focussing on activity-dependent synaptic release of BDNF. The modality and the site of neurotrophin secretion are dependent on the processing and subsequent targeting of the neurotrophin precursor molecules. Therefore, the available data regarding formation and trafficking of neurotrophins in the secreting neurons are critically reviewed. In addition, we discuss existing evidence that the characteristics of neurotrophin secretion are similar (but not identical) to those of other neuropeptides. Finally, since BDNF has been proposed to play a critical role as an intercellular synaptic messenger in long-term potentiation (LTP) in the hippocampus, we try to reconcile this possible role of BDNF in LTP with the recently described features of synaptic BDNF secretion.