Resistance of solid tumors to chemo‐ and radiotherapy remains a major obstacle in anti‐cancer treatment. Herein, the membrane protein caveolin‐1 (CAV1) came into focus as it is highly expressed in many tumors and high CAV1 levels were correlated with tumor progression, invasion and metastasis, and thus a worse clinical outcome. Increasing evidence further indicates that the heterogeneous tumor microenvironment, also known as the tumor stroma, contributes to therapy resistance resulting in poor clinical outcome. Again, CAV1 seems to play an important role in modulating tumor host interactions by promoting tumor growth, metastasis, therapy resistance and cell survival. However, the mechanisms driving stroma‐mediated tumor growth and radiation resistance remain to be clarified. Understanding these interactions and thus, targeting CAV1 may offer a novel strategy for preventing cancer therapy resistance and improving clinical outcomes. In this review, we will summarize the resistance‐promoting effects of CAV1 in tumors, and emphasize its role in the tumor‐stroma communication as well as the resulting malignant phenotype of epithelial tumors.