Sex differences in sports performances continue to attract considerable scientific and public attention, driven in part by high profile cases of: 1) biological male (XY) athletes who seek to compete in the female category after gender transition, and 2) XY athletes with medical syndromes collectively known as disorders or differences of sex development (DSD). In this perspective we highlight scientific evidence that informs eligibility criteria and applicable regulations for sex categories in sport. There are profound sex differences in human performance in athletic events determined by strength, speed, power, endurance, and body size such that males outperform females. These sex differences in athletic performance exist before puberty and increase dramatically as puberty progresses. The profound sex differences in sports performance are primarily attributable to the direct and indirect effects of sex-steroid hormones and provide a compelling framework to consider for policy decisions to safeguard fairness and inclusion in sports.