IN 2002, THE WOMEN’S HEALTH INITIATIVE (WHI) RANdomized trial of placebo vs hormone therapy with estrogen and progestin was stopped early because of evidence of harm. Sales of combined estrogen-progestin plummeted 32% between the period immediately before the study’s release and the analogous period 1 year later, as the WHI trial had shown that hormone therapy increased a woman’s risk of breast cancer and myocardial infarction. The finding contradicted decades of case-control and observational cohort studies that had suggested that hormone therapy was associated with strong protective effects on the cardiovascular system. The WHI results also undermined a long and successful campaign by hormone replacement advocates to present hormone therapy as a panacea against heart disease, loss of femininity, and other perils of aging. In the scientific community, the WHI results became “exhibit 1” for critics of observational studies, who argued that this latest upheaval of conventional medical knowledge proved (once again) that only randomized studies can yield useful insights into cause and effect. Eight years hence, and many subgroup analyses later, a more nuanced explanation for the study’s findings has emerged. Among the few women in the WHI who enrolled around the time of their menopause, hormone therapy with both estrogen and progestin did not increase the risk of cardiovascular disease and may have reduced it slightly. However, most women in the study were well past menopause at enrollment (the average age was 63 years), and the negative effects of hormone therapy, which increase with more elapsed time after menopause, exceeded any small benefits that might have been experienced by the younger women in the study. In addition, the WHI documented numerous other negative effects of hormone therapy, including an increased risk of stroke and pulmonary embolism, which are not strongly associated with the timing of hormone therapy initiation. Ultimately, the only long-term benefit of hormone therapy that the US Food and Drug Administration (FDA) allows the manufacturer to claim is reduction of risk of osteoporotic fractures. That breast cancer rates in the WHI increased among women receiving hormone therapy was not surprising. Epidemiological and biological studies had anticipated the effect, although the magnitude of risk was not known until the WHI, which showed that the effect of hormone therapy on breast cancer risk was about the same as the deleterious effect on cardiovascular health. In each case, 42 more of approximately 8000 women in the hormone therapy group than the placebo group experienced the adverse outcome. Put in a population perspective, this means that the absolute increase in risk was only approximately 0.5% over the course of the study. But what may seem like a small effect in the study apparently turned out to be an enormous effect in the population. Several years after use of hormone therapy plummeted in the United States, breast cancer incidence also declined. Other questions lingered. What, if at all, is the effect of hormone therapy on the type of breast cancer a woman develops? Are there differences in the aggressiveness or in the potential treatability of cancers caused by hormone therapy? Several observational studies suggested that hormone therapy had counterbalancing actions in that it caused more breast cancers, but on average those cancers were less advanced and had more favorable prognostic features, such as being more often estrogen receptor positive. This potential trade-off made the ultimate effect of the increase in incidence on the rate of death from breast cancer uncertain. Other questions involved the relation between duration of use of hormone therapy and increase in breast cancer risk. Would shorter periods of hormone therapy be associated with less risk? Would the risk decrease after cessation of hormone therapy or remain elevated for a sustained period? In this issue of JAMA, Chlebowski et al report results of an 11-year follow-up of WHI estrogen-progestin trial participants that address many of these questions. The