Colorectal cancer (CRC) represents the third most common cancer type worldwide and is a leading cause of cancer-related mortality in the US and Western countries. Rodent models have been invaluable to study the etiology of CRC and to test novel chemoprevention avenues. In the past, the laboratory mouse has become one of the best preclinical models for these studies due to the availability of genetic information for commonly used mouse strains with well-established and precise gene targeting and transgenic techniques. Well-established chemical mutagenesis technologies are also being used to develop mouse and rat models of CRC for prevention and treatment studies. In addition, xenotransplantation of cancer cell lines and patient derived xenografts (PDX) have been useful for preclinical prevention studies and drug development. This review focuses on the recent use of rodent models to evaluate the utility of novel strategies in the prevention of colon cancers including immune prevention approaches and the manipulation of the intestinal microbiota.