For regulated secretion, mast cells and several other cell types utilize compound exocytosis, a combination of granule-plasma membrane and granule-granule fusions. The molecular machinery that controls this massive export process has not been identified. We report that SNAP-23, a t-SNARE related to SNAP-25, relocates in response to stimulation from plasma membrane lamellipodia-like projections to granule membranes in permeabilized mast cells. While relocation is a prerequisite for secretion, it can occur without membrane fusion and will expedite a subsequent secretory response. After relocation, SNAP-23 is required for exocytosis, implying a crucial role in promoting membrane fusion. Thus, relocation of this SNARE regulates compound exocytosis and links granule-plasma membrane and granule-granule fusions.