There is increasing evidence that sex-specific differences in toxicity profiles and outcome after radiotherapy are accumulating in medical oncology, and that treatment strategies may require some modification. Furthermore, sex-specific differences in the sensitivity to genotoxic and therapeutical agents are also of general concern for risk estimation. This review is focussed on the specific influence of sex on these endpoints covering both a clinical and a biological point of view. In this paper, the literature was systematically reviewed with respect to sex-specific differences in tumor and normal tissue sensitivity after exposure to ionizing radiation, as well as to the relevant underlying molecular and cellular mechanisms. Although a number of data on sex-specific differences are available and remarkable differences on clinical, molecular, and cellular levels have been reported, a firm conclusion on any existing sex-specific differences is not yet possible. Future studies are required and should be focussed on this aspect of individual radiosensitivity.