Accumulation of filamentous actin (F-actin) at the immunological synapse (IS) is a prerequisite for the cytotoxic function of natural killer (NK) cells. Subsequent to reorganization of the actin network, lytic granules polarize to the IS where their contents are secreted directly toward a target cell, providing critical access to host defense. There has been limited investigation into the relationship between the actin network and degranulation. Thus, we have evaluated the actin network and secretion using microscopy techniques that provide unprecedented resolution and/or functional insight. We show that the actin network extends throughout the IS and that degranulation occurs in areas where there is actin, albeit in sub-micron relatively hypodense regions. Therefore we propose that granules reach the plasma membrane in clearances in the network that are appropriately sized to minimally accommodate a granule and allow it to interact with the filaments. Our data support a model whereby lytic granules and the actin network are intimately associated during the secretion process and broadly suggest a mechanism for the secretion of large organelles in the context of a cortical actin barrier.