OBJECTIVE: The history of the discovery of mechanisms contributing to sex difference helps to better appreciate gender factors in a variety of disease states. The objective of this article is to illustrate four mechanisms of sex differences in disease incidence: X-linkage (including inactivation, escape from inactivating, skewed inactivation), sex-specific exposure to disease-producing pathogens, fetal microchimerism, and iron depletion. METHODS: This is a historic review. RESULTS: An emphasis on sex difference led to the uncovering of four different mechanisms by which illness rates differ in men and women. CONCLUSIONS: Research into many disease states can benefit from a focus on potential mechanisms that yield sex differences in illness susceptibility, progression, and outcome.