Tissue destruction in immune-mediated disease requires more than the presence of antigen-specific lymphocytes. Lessons from type 1 diabetes and celiac disease show that loss of tolerance—marked by autoreactive or dietary antigen–specific Th1 responses—is necessary but not sufficient for pathology. The magnitude of the CD4⁺ T-cell response, and the signals that amplify it, are decisive because they provide the “license” enabling cytotoxic CD8⁺ T cells (CTLs) to kill. Notably, antigen-specific CTLs can persist in tissues without causing injury unless they receive additional cues. These licensing signals differ from those in lymph nodes and include stress-induced non-classical MHC ligands, NK receptor engagement, and cytokines such as IL-15. This framework helps explain why tumor-specific CTLs often fail to clear cancers and suggests that, beyond checkpoint inhibition, therapies must also target the pathways that license CTLs to execute tissue destruction.