Cytotoxic cells form a conjugate with their target to form an immunologic synapse, followed by trafficking of the cytotoxic granules containing perforin and granzymes toward the immunologic synapse, docking, priming, and fusion of the cytotoxic granules with the plasma membrane. Granule content is released into the immunologic synapse and induces target-cell destruction by caspase-dependent and -independent apoptosis. Except for XLP and some congenital immunodeficiencies, all known genetic HLH is due to defects in proteins essential for this process.