AbstractThe molecular mediators present within the inflammatory microenvironment are able, in certain conditions, to favor the initiation of tertiary lymphoid structure (TLS) development. TLS is organized lymphocyte clusters able to support antigen‐specific immune response in non‐immune organs. Importantly, chronic inflammation does not always result in TLS formation; instead, TLS has been observed to develop specifically in permissive organs, suggesting the presence of tissue‐specific cues that are able to imprint the immune responses and form TLS hubs. Fibroblasts are tissue‐resident cells that define the anatomy and function of a specific tissue. Fibroblast plasticity and specialization in inflammatory conditions have recently been unraveled in both immune and non‐immune organs revealing a critical role for these structural cells in human physiology. Here, we describe the role of fibroblasts in the context of TLS formation and its functional maintenance in the tissue, highlighting their potential role as therapeutic disease targets in TLS‐associated diseases.