Genetically engineered mice are essential tools in both mechanistic studies and drug development in colon cancer research. Mice with mutations in the Apc gene, as well as in genes that modify or interact with Apc, are important models of familial adenomatous polyposis. Mice with mutations in the β-catenin signaling pathway have also revealed important information about colon cancer pathogenesis, along with models for hereditary nonpolyposis colon cancer and inflammatory bowel diseases associated with colon cancer. Finally, transplantation models (xenografts) have been useful in the study of metastasis and for testing potential therapeutics. This review discusses what models have been developed most recently and what they have taught us about colon cancer formation, progression, and possible treatment strategies.