Radiotherapy (RT) based on X-ray irradiation is a widely applied cancer treatment strategy in the clinic. However, treating cancer based on RT alone usually results in insufficient radiation energy deposition, which inevitably has serious side effects on healthy parts of the body. Interestingly, high atomic number (high-Z) metal nanocrystals as X-ray sensitizers can reduce the radiation dose effectively due to their high X-ray absorption, which has attracted increased attention in recent years. High-Z metal nanocrystals produce Auger and photoelectrons electrons under X-ray irradiation, which could generate large amounts of reactive oxygen species, and induce cellular damages. The sensitization effect of high-Z metal nanocrystals is closely related with their composition, morphologies, and size, which would strongly impact their performances in the application of cancer imaging and therapy. In this review, we summarize diverse types of X-ray sensitizers such as bismuth, hafnium, gold, and gadolinium for cancer RT and imaging applications. In addition, current challenges and the outlook of RT based on high-Z metal nanocrystals are also discussed.