Sex significantly influences the clinical and pathological characteristics of colorectal cancer (CRC). These include differences in incidence and mortality rates, clinical presentations including age, emergency surgery for complications from CRC, screening participation rates, site, stage and treatment utilization, histopathology and survival. Environmental, behavioral and biological factors contribute to the differential risk. Recent advances in the molecular biology of CRC, specifically in microsatellite status, estrogen hormone and estrogen receptor beta, have led to greater understanding of the effect of estrogen in colorectal carcinogenesis. Estrogen may preferentially protect against microsatellite unstable cancers through its effect on selected molecular targets; however, the exact pathways have not been elucidated. Recognition of important sex disparities in these areas may lead to the implementation of specific measures to diminish these differences and facilitate equitable distribution of health resources. Identifying specific molecular targets on CRC that interact with estrogen may stimulate research to improve the overall outcomes of all patients with CRC.