Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of proteins that are known to serve important functions in the differentiation and survival of neurons and in the activity-dependent modification of synapses. BDNF is synthesized, sorted to large-dense core vesicles, and transported to both axons and dendrites. Secretion of BDNF from the axonal terminal and the dendrite can serve as anterograde and retrograde signals at the synapse, respectively, for trophic regulation of post- vs. presynaptic neurons, as well as for the induction of activity-dependent synaptic modification. How activity regulates axonal and dendritic release of BDNF is largely unknown. Using cultured hippocampal neurons expressing fluorescent protein-tagged BDNF, we found that a train of action potentials triggers differential modes of secretion of BDNF in axons and dendrites. Our results suggest that neurons may utilize different vesicle fusion mechanisms to regulate the amount and time course of secreted BDNF.