Depletion of a pool of readily releasable vesicles during repetitive presynaptic activity is a candidate mechanism for the induction of short-term synaptic depression. The large, calyx-type synaptic terminals in the brainstem auditory pathway, and especially the calyx of Held, offer unique possibilities for studying the cellular mechanisms leading to synaptic depression. Recent work at these synapses using presynaptic whole-cell patch-clamp recordings has revealed a large pool of readily releasable vesicles. During prolonged presynaptic depolarization, vesicles are released in kinetically distinct phases, indicating heterogeneity of release probability between vesicles. Heterogeneity might endow synapses with a rapid phase of depression at the onset of activity, followed by sustained and surprisingly large synaptic strength during the steady-state phase of depression. By influencing the synaptic output during repetitive activity, vesicle pool dynamics are expected to modulate information processing in neuronal networks of the CNS.