Evidence of sex-related disparities in the care and outcomes of patients with acute coronary syndrome (ACS) emerged >30 years ago, and yet the mechanisms behind these sex-specific differences remain unclear. In this Review, we discuss the current literature on differences between women and men in the clinical presentation, pathophysiology, evaluation, management, and outcomes of ACS. Although the symptoms of ACS and the benefits of therapy generally overlap between women and men, women continue to receive less-aggressive invasive and pharmacological therapy than men. In addition, young women in particular have worse short-term and long-term outcomes than men. To understand better the mechanisms behind these continued disparities, we have identified areas of future research that need to be urgently addressed in fields that range from clinical evaluation and management, to increasing representation of women in research.