At nerve terminals, neurotransmitter release is mediated by exocytosis of synaptic vesicles at active zone. After exocytosis, vesicular components are efficiently retrieved by endocytosis. Tight coupling between synaptic vesicle exocytosis and endocytosis is critical for the maintenance of neurotransmission at central synapses. Recently, we have developed a new fluorescent pH reporter that permits us to examine exocytosis-endocytosis coupling at the level of individual synaptic vesicles at hippocampal synapses.1 To our surprise, we observed that the tight coupling of exocytosis and endocytosis broke down at very low stimulation frequencies, resulting in the generation of two endocytic vesicles per single exocytic fusion event. As stimulation frequency increased, exocytosis-endocytic coupling was restored with one endocytic vesicle generated for each vesicle exocytosed. Further studies revealed that the dissimilar patterns of exocytosis-endocytic coupling at different stimulation frequencies were mediated by two pathways of endocytosis that are orchestrated during differential patterns of neuronal activity.1 Here, we summarize our observations and further discuss their possible implications.