Developments in the diagnosis and treatment of colorectal cancer (CRC) have been made in the last decade, but the overall survival rate of patients with CRC has not improved dramatically. Genetic and epigenetic events contribute to CRC pathogenesis. Tumor heterogeneity results in a range of prognoses and responses to CRC management and therapy. Epigenetic biomarkers have potential in CRC diagnosis and in measuring response to therapy. Combining information from genetic and epigenetic alterations provides an opportunity to predict response to therapy. Epigenetic biomarkers can be used in disease stratification, which also helps in designing therapeutic approaches for CRC. Challenges in the understanding of CRC development and gaps in knowledge are discussed.