Sex differences have traditionally been attributed to gonadal hormones, but accumulating evidence shows that sex chromosomes exert distinct, cell-autonomous effects on health, aging, and disease. XX and XY complements alter gene dosage, epigenetic programming, immune signaling, metabolism, and cellular stress responses, which shape aging and disease trajectories in women and men. This Review integrates mechanistic advances in sex chromosome biology—including escape from X chromosome inactivation, X reactivation, parent-of-X-origin, X-skew, X-and Y-linked gene functions, and Y loss—with aging, neurologic disease, immunity, cancer, and cardiometabolic disease.