Abstract Colorectal cancer (CRC) is the third most prevalent and second deadliest cancer in the U.S. with 135,430 cases and 50,260 deaths in 2017. Its pathogenesis stems from genetic susceptibility coupled with environmental interactions in the colon and rectum that synergize ideal conditions for neoplastic growth, initially from benign adenomatous polyps that might progress to carcinoma over several years. However, there is a disparity in morbidity and mortality among races, with African Americans demonstrating the highest incidence and mortality rates and a distribution of cancer that favors metastatic disease at presentation. The causes are likely multifactorial and include environmental factors that directly or indirectly influence the colonic epithelium and stem cells to be primed to commence the neoplastic process; societal factors such as socioeconomic class and access to health insurance; biologic factors such as earlier age development of adenomas and more proximal colon distribution of cancers or the gut microbiome; genetic factors such as higher frequency of somatic KRAS mutations that increase the aggressiveness of CRCs and shifts of the type of microsatellite instability that affect outcome; and immunologic factors such as less granzyme B-expressing T cells within CRCs. Most of these observations have just come in the past 10 years of research. Further biologic studies on environmental and genetic influences would be enhanced with adequate biorepository sources for CRC specimens from a variety of racial backgrounds, as most published data are not obtained from diverse specimens. CRC is preventable, and there is evidence that enhanced screening rates among African Americans can reduce or abolish the observed disparity. The 2017 U.S. Multi-Society Task Force on Colorectal Cancer for the first time included race as a factor in their screening recommendations, moving African Americans from age 50 years to age 45 years to commence CRC screening. Other opportunities to reduce the disparity include improved provider and patient education for screening and patient navigation for screening. Including a diverse population for trials of CRC screening, genome-wide association and other genetic studies, and treatment trials would further identify unique issues for higher-risk populations. Citation Format: John M. Carethers. Colorectal cancer [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr IA02.