Purpose of reviewDespite the large investment of resources from screening, the fact that colorectal cancer remains the second leading cause of cancer deaths among Americans underscores the need for alternative strategies. Thus, a major clinical and research imperative is personalize clinical care, while focusing on risk stratification for screening, surveillance, chemoprevention, and therapeutic intervention.Recent findingsA complicating factor that colorectal cancer is biologically heterogeneous for at least four consensus molecular subtypes presents clear challenges for developing robust molecular biomarkers.SummaryThe purpose of the review is to discuss the genetics and molecular biology of colonic neoplasia, high and low penetrance, and racial disparities in colonic neoplasia. Finally, we put forth the emerging concept of greater genomic landscape and the idea of chromatin protection therapy as a novel adjuvant to chemotherapy.