Cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment (TME) with diverse functions such as extracellular matrix (ECM) remodeling, modulation of metabolism and angiogenesis, and crosstalk with both cancer cells and infiltrating immune cells by production of growth factors, cytokines, and chemokines. Within the TME milieu, CAFs exhibit morphological and functional transitions with relatively specific markers and hold tremendous potential to facilitate tumorigenesis, development, and resistance towards multiple therapeutic strategies including chemotherapy, radiotherapy, targeted therapy, anti-angiogenesis therapy, immunotherapy, and endocrine therapy. Accordingly, CAFs themselves and the downstream effectors and/or signaling pathways are potential targets for optimizing the sensitivity of anti-cancer therapies. This review aims to provide a detailed landscape of the role that CAFs play in conferring therapeutic resistance in different cancers and the underlying mechanisms. The translational and therapeutic perspectives of CAFs in the individualized treatment of malignant tumors are also discussed.