Objective To summarize the key roles of cancer-associated fibroblasts (CAFs) in the pathogenesis, development, therapeutic resistance, and immune microenvironment modulation of colorectal cancer (CRC). MethodsThrough a systematic review of existing literature, this article summarizes the origin and heterogeneity of CAFs, their mechanisms of action in CRC occurrence and progression, and reviews potential CAFs-targeting therapeutic strategies. ResultsCAFs are heterogeneous with respect to both origin and function. As a critical ingredient in tumor microenvironment, CAFs drive CRC progression by promoting tumor proliferation, invasion, metastasis, angiogenesis. CAFs can mediate therapy resistance by regulating cancer stem cell properties and suppress antitumor immunity by regulating immune checkpoint molecules. Targeting specific CAFs subsets or their key signaling pathways demonstrat tumor-suppressive effects. ConclusionsCAFs are key regulators of CRC progression. Developing targeted therapeutic strategies against their origins, heterogeneity, and functional mechanisms holds the potential to providing new directions in CRC treatment.