Cytotoxic lymphocytes are major players that eliminate transformed tumor cells or cells infected with intracellular pathogens.In this process, pore-forming protein perforin and cytotoxic protease granzymes (Gzms) are released from their granules into the immunological synapse formed between cytotoxic cells and their targets.Gzms are a highly conserved set of serine proteases.After they are delivered into target cells by perforin, they can cleave cellular or viral proteins, leading to the destruction of target cells or inhibition of viral replication.Humans express five Gzms (A, B, K, H, and M).Because GzmA and B are the most abundant proteases of the Gzm family in humans and mice, their functions have been extensively investigated.Recently,we have defined some roles of orphan Gzms (H, K, and M) against tumors and viruses.We demonstrated that GzmK targets the SET complex to initiate caspase-independent cell death.GzmK can induce the rapid generation of reactive oxygen species (ROS) through a Bid-dependent pathway.