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Colorectal cancer (CRC) is among the most prevalent cancers worldwide and represents a major public health challenge in the developed world. From the perspective of translational investigation, scientists have enormous opportunity to elucidate the molecular genetic mechanisms that contribute to CRC pathogenesis because most cancers develop from adenomatous precursor lesions. The process of adenoma growth and transformation is accompanied by cumulative mutations in dominant genetic pathways that confer a growth advantage. Although this developmental process permits interrogation of informative pathways before the development of cancer, only a few adenomas progress to CRC. Accordingly, a major challenge for clinical translational investigators is to identify the molecular signatures that indicate increased likelihood for adenoma progression. By corollary, these molecular signatures include mutations in high penetrance alleles, which include the Adenomatous Polyposis Coli (APC) gene as well as other alleles in the Wnt/β-catenin signaling pathway that specify increased genetic susceptibility to CRC. Interactions between these high penetrance alleles and other modifier genes as well as with environmental factors are of particular importance to understand the complex network of events that lead to CRC. This brief review will highlight 3 areas where important questions concerning genetic and environmental risk factors have fueled translational investigation into possible pathways that lead to CRC.