Colorectal cancer (CRC) is the second-most lethal cancer in the United States, causing 50,000 deaths annually. Cancer is caused by alterations in genetic material called mutations; however, correcting such changes remains unfeasible. Additionally, non-genetic structural and chemical changes are essential for cancer to gain aggressive growth potential and evading therapy. Although such non-genetic changes are essentially reversible using therapeutic drugs, details of how and when they occur during CRC progression remains unknown. Using cutting-edge human CRC and mouse model systems, we will characterize the non-genetic changes during CRC growth and identify novel factors that can be targeted for innovative therapies.