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Adoptive immunotherapy with virus-specific cytotoxic T cells (VSTs) has evolved over the last three decades as a strategy to rapidly restore virus-specific immunity to prevent or treat viral diseases after solid organ or allogeneic hematopoietic cell-transplantation (allo-HCT). Since the early proof-of-principle studies demonstrating that seropositive donor-derived T cells, specific for the commonest pathogens post transplantation, namely cytomegalovirus or Epstein-Barr virus (EBV) and generated by time- and labor-intensive protocols, could effectively control viral infections, major breakthroughs have then streamlined the manufacturing process of pathogen-specific T cells (pSTs), broadened the breadth of target recognition to even include novel emerging pathogens and enabled off-the-shelf administration or pathogen-naive donor pST production. We herein review the journey of evolution of adoptive immunotherapy with nonengineered, natural pSTs against infections and virus-associated malignancies in the transplant setting and briefly touch upon recent achievements using pSTs outside this context., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)