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Tissue-resident memory T (T_RM) cells critically contribute to the rapid immunoprotection and efficient immunosurveillance against pathogens, particularly in barrier tissues, but also during anti-tumor responses. However, the involvement of T_RM cells also in the induction and exacerbation of immunopathologies, notably in chronically relapsing auto-inflammatory disorders, is becoming increasingly recognized as a critical factor. Thus, T_RM cells may also represent an attractive target in the management of chronic (auto-) inflammatory disorders, including multiple sclerosis, rheumatoid arthritis, celiac disease and inflammatory bowel diseases. In this review, we focus on current concepts of T_RM cell biology, particularly in the intestine, and discuss recent findings on their involvement in chronic relapsing–remitting inflammatory disorders. Potential therapeutic strategies to interfere with these T_RM cell-mediated immunopathologies are discussed.