During intense presynaptic activity, the readily releasable pool (RRP) of synaptic vesicles empties more quickly than it can be refilled, and short-term depression results. Ordinarily, the pool refills within 20 s, but long, high-frequency trains of action potentials often induce a form of short-term depression that persists for a much longer time. Here, we report that replenishment of the RRP is governed by two simple processes: the previously identified mechanism termed refilling, and another process that appears after extensive exocytosis and produces a transient decrease in the capacity of the pool, lasting for several minutes. The data presented here place stringent constraints on the types of kinetic models that can be used to describe synaptic vesicular cycling and are inconsistent with the traditional multipool models of vesicular mobilization.