In this episode, we unpack a landmark study that settles a decades-long debate over how synaptic vesicles release neurotransmitters—introducing the “kiss-shrink-run” pathway as the dominant mechanism in hippocampal synapses. Guided by host commentary, we explore how time-resolved cryo–electron tomography paired with millisecond optogenetic stimulation captured over 1,000 tomograms to reveal a rapid sequence: vesicles briefly “kiss” the membrane within 4 ms, form a ~4 nm fusion pore and “shrink” to about half their surface area to expel neurotransmitters, then “run” by detaching within tens of milliseconds for hyperfast recycling. We discuss how this reconciles the kiss-and-run and full-collapse models, explains high-fidelity, high-throughput synaptic transmission (accounting for over 80% of release events), and sets a new standard for in situ membrane dynamics. The episode also highlights the foundational contributions of corresponding author Professor Guo-Qiang Bi, from dissecting synaptic network dynamics to advancing cryo-ET for nanoscale visualization—work that paved the way for this breakthrough published in Science.