Brain-derived neurotrophic factor (BDNF) and other members of the protein family of neurotrophins have been implicated in a multitude of processes that are important for neuronal development and synaptic plasticity in the rodent central nervous system. In comparison to the wealth of information available with respect to the biological functions of neurotrophins, our knowledge regarding the processes that govern synaptic secretion of neurotrophins is scarce. Using live cell imaging of GFP-tagged neurotrophins in primary neurons, immunocytochemical detection of endogenous BDNF in fixed cells, and by blocking the action of endogenously released BDNF by means of TrkB receptor bodies in living neurons, several studies in recent years have allowed to better understand the time course and the mechanisms of synaptic secretion of neurotrophins. This review will summarize the current knowledge regarding the intracellular processing of proneurotrophins, the targeting of neurotrophin vesicles to axons and dendrites, and the mechanisms of activity-dependent secretion of BDNF at synapses. Since these processes are known to be cell type dependent, special emphasis is given to observations gained from experiments in primary neurons.