Radiotherapy (RT) is one of the most common and effective clinical therapies for malignant tumors. However, there are several limitations that undermine the clinical efficacy of cancer RT, including the low X-ray attenuation coefficient of organs, serious damage to normal tissues, and radioresistance in hypoxic tumors. With the rapid development of nanotechnology and nanomedicine, high-Z nanoradiosensitizers provide novel opportunities to overcome radioresistance and improve the efficacy of RT by deposition of radiation energy through photoelectric effects. To date, several types of nanoradiosensitizers have entered clinical trials. Nevertheless, the limitation of the single treatment mode and the unclear mechanism of nanoparticle radiosensitization have hindered the further development of nanoradiosensitizers. In this review, we systematically describe the interaction mechanisms between X-rays and nanomaterials and summarize recent advances in multifunctional high-Z nanomaterials for radiotherapeutic-based multimodal synergistic cancer therapy. Finally, the challenges and prospects are discussed to stimulate the development of nanomedicine-based cancer RT.