Although physicians have attempted for centuries to uncover the biological differences between men and women with regard to mental illness, they continue to face the challenges of untangling biological factors from social and cultural ones. This article uses examples from history to illustrate three common problems in trying to establish biological differences: identifying factors as sex-based when they are really gender-based; overlooking changes in masculine and feminine roles over time; and placing too great an emphasis on hormones. By using the benefit of hindsight to identify problems from the past, we can think more critically about these issues in the present and the future.