Before age 65, women have less heart disease than men. For many years, estrogen was the most popular explanation for this female advantage, and observational studies through the 1980s showed a lower risk of heart attacks in postmenopausal women taking “replacement” estrogen. But the Women’s Health Initiative (WHI), the first placebo-controlled trials of hormone therapy with the size and statistical power necessary to study clinical cardiovascular outcomes, did not confirm the hormone-healthy heart hypothesis. Now, at least 5 years later, the most unexpected WHI result may be how resilient the estrogen hypothesis has been. Where, beyond estrogen therapy, should we go from here to explain the striking sex differences in heart disease rates? A broader spectrum of research about the female cardiovascular advantage and its translation is needed.