Colorectal cancer (CRC) is one of the leading cancers and cause of cancer deaths in American women and men. Females and males share a similar lifetime cumulative risk of CRC however, substantial differences in risk factors, tumor biology, and effectiveness of cancer prevention services have been observed between them. This review distills the evidence documenting the unique variation observed between the genders relating to CRC risk factors, screening and prevention. Consistent evidence throughout the world demonstrates that women reach equivalent levels of adenomas and CRC as men but it occurs nearly a decade later in life than in their male counterparts. Women have a higher proportion of tumors which are hypermethylated, have microsatellite instability and located in the proximal colon suggesting the serrated pathway may be of greater consequence in them than in men. Other CRC risk factors such as smoking, diet and obesity have been shown to have disparate effects on women which may related to interactions between estrogen exposure, body fat distribution, and the biologic underpinnings of their tumors. There is data showing the uptake, choice, and efficacy of different CRC screening methods in women is dissimilar to that in men. The mortality benefit from FOBT, sigmoidoscopy, and protection from interval CRC by colonoscopy appears to be lower in women than men. A greater understanding of these gender idiosyncrasies will facilitate an personalized approach to CRC prevention and should ultimately lead to a reduced burden of disease.