Tissue-resident memory T cells (TRM) afford superior immune protection against a wide variety of infections and cancer, and are increasing implicated in driving autoimmune disease. Despite this, targeting TRM therapeutically is currently difficult, as our knowledge of their developmental requirements is incomplete. We and others have shown that TRM are distinct from other memory T cell subsets in terms of their gene expression, tissue distribution, regulatory cues and function. However, the majority of this work has been performed in animal models, leaving how TRM develop and function in human tissues unclear. Using difficult-to-access organ donor tissues and patient cohorts, we are investigating the survival and functional pathways of human TRM and determining how these pathways are altered in protective and pathogenic immunity. Combined, this work will provide a molecular framework for human TRM function and survival, revealing novel molecular pathways that may be safely targeted therapeutically.