An individual's sex has been long recognized as a key factor affecting cancer incidence, prognosis, and treatment responses. However, the molecular basis for sex disparities in cancer remains poorly understood. We performed a comprehensive analysis of molecular differences between male and female patients in 13 cancer types of The Cancer Genome Atlas and revealed two sex-effect groups associated with distinct incidence and mortality profiles. One group contains a small number of sex-affected genes, whereas the other shows much more extensive sex-biased molecular signatures. Importantly, 53% of clinically actionable genes (60/114) show sex-biased signatures. Our study provides a systematic molecular-level understanding of sex effects in diverse cancers and suggests a pressing need to develop sex-specific therapeutic strategies in certain cancer types.