Regulatory T (Treg) cells, known for their immunosuppressive functions, have recently been shown to produce pro-repair mediators that are critical for tissue repair and regeneration. This review examines the interactions between Treg cells and tissue-resident non-immune cells, including epithelial, mesenchymal, and endothelial cells, in the context of tissue repair, fibrosis, and cancer. Treg cells promote tissue repair through distinct modalities: indirectly by limiting collateral tissue damage through immunosuppressive molecules acting on immune cells, and directly by producing tissue factors that are sensed by mesenchymal, epithelial, and endothelial cells. These interactions generate context- and tissue-specific repair programs. The review highlights the role of Treg cell-derived mediators such as amphiregulin (Areg), fibroblast growth factor 7 (FGF7), and transforming growth factor-β (TGF-β) in mediating these interactions. Additionally, it discusses the potential for Treg cells to "anchor" themselves in tissues to optimize interactions with tissue cells. The review also explores the impact of damage-associated signals, such as IL-18 and IL-33, on Treg cell reparative function. Finally, it examines the role of Treg cells in chronic diseases and cancer, particularly in fibrosis and cancer-associated stromal cell interactions. Overall, the interplay of Treg cells with non-immune cells offers new insights into mechanisms that maintain tissue integrity and could lead to therapeutic targets for human diseases.Regulatory T (Treg) cells, known for their immunosuppressive functions, have recently been shown to produce pro-repair mediators that are critical for tissue repair and regeneration. This review examines the interactions between Treg cells and tissue-resident non-immune cells, including epithelial, mesenchymal, and endothelial cells, in the context of tissue repair, fibrosis, and cancer. Treg cells promote tissue repair through distinct modalities: indirectly by limiting collateral tissue damage through immunosuppressive molecules acting on immune cells, and directly by producing tissue factors that are sensed by mesenchymal, epithelial, and endothelial cells. These interactions generate context- and tissue-specific repair programs. The review highlights the role of Treg cell-derived mediators such as amphiregulin (Areg), fibroblast growth factor 7 (FGF7), and transforming growth factor-β (TGF-β) in mediating these interactions. Additionally, it discusses the potential for Treg cells to "anchor" themselves in tissues to optimize interactions with tissue cells. The review also explores the impact of damage-associated signals, such as IL-18 and IL-33, on Treg cell reparative function. Finally, it examines the role of Treg cells in chronic diseases and cancer, particularly in fibrosis and cancer-associated stromal cell interactions. Overall, the interplay of Treg cells with non-immune cells offers new insights into mechanisms that maintain tissue integrity and could lead to therapeutic targets for human diseases.