Radiotherapy (RT) has been extensively applied in clinical cancer therapy. However, cancer cells usually exhibit high resistance to radiation, ultimately resulting in the failure of tumor eradication. Recently, a series of radiosensitizers that can selectively accumulate into specific organelles inside cancer cells have been developed, providing new opportunities for overcoming radioresistance and boosting radiosensitivity. In this Review, the progress and future directions of organelle-targeted radiosensitizers will be introduced, which aims to offer valuable information toward better-designed radiosensitizers for clinical cancer therapy.