Colorectal cancer (CRC) is the third most common cancer among Americans, and the second deadliest. Its pathogenesis results from an interplay between environmental factors that influence biological behavior of colonic stem cells, and the genetic makeup of susceptible individuals. Activation of stem cell proliferation from this interplay eventually yields adenomatous polyps, which if not removed after detection through an effective screening program, may further progress to cancers that may metastasize and affect survival. This normal-to-polyp-to-cancer process appears to occur at different initiation ages and progresses at different rates among various races in the United States, with African Americans demonstrating the highest incidence and mortality for CRC among all races. Compared with Caucasians, African American CRC patients tend to present at a younger age, have a more proximal cancer, present with more advanced stage, and show shortened survival. In parallel, African Americans demonstrate higher risk adenomatous polyps and more proximally-located polyps than Caucasians as the precursor lesions to CRC. There are likely multifactorial factors that contribute to this disparity, including socio-economic, health insurance, and educational factors, CRC screening utilization, diet, obesity, and microbiome makeup of the colon, tobacco utilization, use of NSAIDs and hormone replacement therapy, and differences in biology of the tumor and/or metastasis. Increasing CRC screening rates towards 80% utilization or greater for African Americans suggests that this disparity may be lessened or disappear. Other strategies such as enhanced patient and physician education and patient navigation for colonoscopy may also reduce the disparity. The U.S. Multi-Society Task Force on Colorectal Cancer, for the first time as of July 2017, endorsed lowering the screening age for African Americans from 50 years of age to 45 years of age, an age where the proportion of CRCs below age 45 years matches the proportion of CRCs among Caucasians below 50 years of age. Employment of these and other strategies may further mitigate the observed disparities.