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Cancer-associated fibroblasts (CAFs) are one of the main components of the tumor microenvironment (TME) of solid tumors. They have several functions, which all contribute to tumor growth and immune evasion. CAF presence is associated with poor clinical response to standard therapy and immunotherapy. However, its heterogeneity blunts their understanding and functionality. New analytical techniques are being applied to better understand their role in cancer. Meanwhile, CAF stratification and their immunomodulatory capabilities are the scope of many studies, also in the context of ionizing irradiation. In that regard, new immunotherapy strategies have set their sights on targeting CAF to modulate the TME into a more immune-stimulating environment. Among the different approaches, CAF depletion, reprogramming, and CAF-directed antibodies and cytokines can be distinguished, supported by substantial preclinical evidence and encouraging, but still preliminary clinical findings, mainly from early-phase (phase I) trials. Additionally, CAF-directed radionuclides have gained interest and are in clinical trials for therapeutic as well as diagnostic purposes. Here we summarize the studies and clinical developments of CAF-targeted therapies alone and in combination with radiotherapy.