Women's health research provides an opportunity to focus on the mechanisms underlying health and disease in both men and women. We propose that differences in risk between men and women and among individual women are primarily determined by biologic factors, such as sex steroid hormone metabolism, anatomy, immunologic function, genetic influences, and the effects of reproduction, interacting with external influences, such as psychologic development, sociocultural environment, and economic status. We provide examples whereby a comparison of disease frequencies between men and women and among women allows a focus on underlying mechanisms of disease. We then demonstrate the importance of posing questions about the genesis of differences in disease frequency.