Studies of patients with familial HLH and related disorders have identified critical genes involved in lytic granule exocytosis. Movement of perforin- and granzyme-containing granules along microtubules towards the interface with target cells is defective in Hermansky Pudlak syndrome II (HP) and X-linked lymphoproliferative syndrome (XLP). In Griscelli syndrome type II (GS), granules polarize, but cannot tether to the plasma membrane. Once tethered, a priming step is required to enable the membrane of secretory granules to fuse with the effector cell membrane prior to release into the lytic synapse. These processes are defective in patients with FHL3 and FHL4, respectively. In FHL2, T and NK cells lack functional perforin and therefore fail to kill target cells, despite normal movement and exocytosis of granules at the lytic synapse. Professional illustration by Paulette Dennis.