The article reviews the crosstalk between fibroblasts and immunocytes in fibrosis, from molecular mechanisms to clinical trials. Fibroblasts, initially considered 'immune neutral' cells, are now recognized as critical immune sentinel cells that regulate immune responses. The interaction between fibroblasts and immunocytes, including macrophages, T lymphocytes, and regulatory T cells, plays a crucial role in fibrosis progression across multiple organs such as the lung, liver, heart, and kidney. Key mediators involved in these interactions include growth factors, cytokines, and chemokines. The review highlights the historical overview of these interactions, the general mechanisms, and the therapeutic targets. For instance, PDGFs/PDGFRs, galectins, and FGFs are identified as critical therapeutic targets. The article also discusses the potential of drug delivery systems, such as extracellular vesicles, to target specific cell types more effectively. Despite significant progress, effective drugs to inhibit fibrosis progression remain elusive, emphasizing the need for further research and development.The article reviews the crosstalk between fibroblasts and immunocytes in fibrosis, from molecular mechanisms to clinical trials. Fibroblasts, initially considered 'immune neutral' cells, are now recognized as critical immune sentinel cells that regulate immune responses. The interaction between fibroblasts and immunocytes, including macrophages, T lymphocytes, and regulatory T cells, plays a crucial role in fibrosis progression across multiple organs such as the lung, liver, heart, and kidney. Key mediators involved in these interactions include growth factors, cytokines, and chemokines. The review highlights the historical overview of these interactions, the general mechanisms, and the therapeutic targets. For instance, PDGFs/PDGFRs, galectins, and FGFs are identified as critical therapeutic targets. The article also discusses the potential of drug delivery systems, such as extracellular vesicles, to target specific cell types more effectively. Despite significant progress, effective drugs to inhibit fibrosis progression remain elusive, emphasizing the need for further research and development.