Colorectal cancer (CRC) accounts for 9.4% of new cancer diagnoses among women world-wide. CRC is the third leading cause of incident cancer among women in the United States and has immense impact on morbidity and mortality. We summarize data on CRC pathogenesis and risk in women. We also review the findings from the Women's Health Initiative (WHI) on CRC risk reduction associated with hormone replacement therapy (HRT) use. We then review observational studies since the WHI which evaluated HRT as a chemopreventive agent for CRC among women. The potential mechanisms behind the association between HRT use and CRC are also reviewed. We then discuss the requirements for implementation of chemopreventive agents, and why HRT should not be used for this indication given current knowledge. Further data on the risk–benefit profile of short-term HRT use are needed and will determine whether there is any future role for HRT use in the chemoprevention of CRC.