Drawing on the ethical principles of the Belmont Report, this chapter critically examines the legacy and current policies and practices in the United States related to the inclusion of women in clinical research. Historically, protectionist policies and practices excluded women from research participation, justified by, for example, reliance on the male norm, male bias, and fears of legal liability resulting from tragic cases of fetal harm. Recognition of the ensuing harms to women’s health from exclusion and underrepresentation in research led to significant policy changes in the 1990s encouraging women’s participation in research. Although the knowledge gap in women’s health is narrowing, significant challenges remain, including the need to develop robust approaches to defining sex and gender, identifying and analyzing sex and gender differences, and acknowledging and addressing intersectionality and women’s health needs across their life spans.