Munc13-4 endocytic recycling is required for the serial killing ability of NK cells. The serial killing model implies that one cytolytic effector can subsequently kill multiple target cells. After target recognition, NK cells form a cytolytic synapse with target cell, where cytolytic granule contents are released. During the cytolytic event, Munc13-4 drives the coalescence of late and recycling endosomes with lytic granule to form the “exocytic vesicles,” which fuse with the plasma membrane. Munc13-4 becomes transiently associated with membrane raft microdomains, followed by its subsequent clathrin/AP2-dependent reinternalization. Our model suggests that Munc13-4 retrieval is required for the replenishment of a pool of endocytic vesicles, allowing the subsequent killing event. Our data indicate that the lack of the PIP5Kγ-dependent PIP2 pool leads to impaired clathrin/AP2–mediated retrieval of endocytic machinery components, thus affecting the ability to kill in an iterative manner.