The role of oestrogen in oncogenesis has been examined extensively, especially in the context of breast cancer, and receptor modulators are an integral part of targeted treatment in this disease. The role of oestrogen signalling in colonic carcinoma is poorly understood. Men are more susceptible than women to colon cancer. Furthermore, hormone-replacement therapy affords an additive protective effect for postmenopausal women, and when these women do develop cancer, they typically have less aggressive disease. The discovery of a second oestrogen receptor (ERbeta) and its over expression in healthy human colon coupled with reduced expression in colon cancer suggests that this receptor might be involved. The underlying mechanism, however, remains largely unknown. In this Review, we discuss the various hypotheses presented in the published literature. We examine the cellular and molecular mechanisms through which oestrogen is purported to exert its protective influence, and we review the evidence available to support these claims.