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Breast cancer remains one of women's greatest concerns. When asked regarding the likelihood of contracting a specific disease, most women believe their greatest risk of death is from breast cancer. Interestingly, we have gone from a time when estrogen was utilized as a treatment regimen in advanced breast cancer, to the current question of hormone replacement therapy increasing the risk of breast cancer. When one searches earlier data, it is noted that estrogen in several different forms, including ethinyl estradiol, as well as DES, was used as a therapeutic agent in the management of advanced breast cancer. Indeed, some of the original trials evaluating tamoxifen for adjunctive treatment of breast cancer used estrogen as the "gold-standard" treatment arm. Numerous publications have attempted to address the relationship between hormone replacement therapy and breast cancer. In the last quarter of a century, at least 50 epidemiological studies have been published, with some studies demonstrating slight increases in patients who used hormone replacement therapy for an extended time, while others demonstrated no evidence of a change in incidence. The "Nurses' Health Study" suggested that current users of hormone replacement therapy of 5 or more years' duration have a relative risk of greater than 1.4. While a well-performed and conceived trial, it suffers from limitations like all other studies. In the same time period, multiple additional studies have cast doubt on the likelihood of hormone replacement therapy markedly increasing the risk of breast cancer. When the multitude of studies is combined, the evidence seems to demonstrate that in ever-use of hormone replacement therapy the increase in relative risk is small. It is interesting that, in almost all studies published (even those demonstrating increases such as the "Nurses' Health Study") discontinuation of 2 to 5 years evaporates the increased risk. This seems biologically implausible, given the prior exposure. A recent study by Sellers et al evaluated over 41,000 patients in a prospective cohort. In this study, they closely evaluated patients who were at a higher risk of breast cancer based on a positive family history in first-degree relatives. Interestingly, they, like others, found that HRT was not associated with a significantly increased incidence of breast cancer, but did note a significantly reduced total mortality rate. When one evaluates the sum total data in the world literature regarding hormone replacement therapy and breast cancer, it is difficult to ascertain that any substantial clinical risk exists with the use of hormone replacement therapy and breast cancer. Multiple ongoing trials, including the Women's Health Initiative-a Prospective Protocol, will help to define better if any appreciable risk exists.