Deaths caused by colorectal cancer (CRC) are among the leading causes of cancer-related death in the United States and around the world. Approximately 150,000 Americans are diagnosed with CRC each year and around 50,000 will die from it. Mutations in many key genes have been identified that are important to the pathogenesis of CRC. Among the genes mutated in CRC, RAS and RAF mutations are common events. Both RAS and RAF are critical mediators of the mitogen-activated protein kinase (MAPK) pathway that is involved in regulating cellular homeostasis, including proliferation, survival, and differentiation. In this review, we provide a historical perspective and update on RAS/RAF mutations as related to colorectal cancer. Additionally, we will review recent mouse models of RAS and RAF mutations that have an impact on CRC research.