Mutations in the adenomatous polyposis coli (APC) gene are pivotal in colorectal tumorigenesis. Existing mouse intestinal tumor models display mainly small intestinal lesions and carcinomas are rare. We defined human CDX2 sequences conferring colon epithelium-preferential transgene expression in the adult mouse. Mice carrying a CDX2P-NLS Cre recombinase transgene and a loxP-targeted Ape allele developed mainly colorectal tumors, with carcinomas seen in 6 of 36 (17%) of mice followed for 300 days. Like human colorectal lesions, the mouse tumors showed biallelic Apc inactivation, beta-catenin dysregulation, global DNA hypomethylation, and aneuploidy. The predominantly distal colon and rectal distribution of tumors seen in mice where one Ape allele was inactivated in epithelial cells from distal ileum to rectum suggests that regional differences in the intestinal tract in the frequency and nature of secondary genetic and epigenetic events associated with adenoma outgrowth have a contributing role in determining where adenomas develop. The presence of large numbers of small intestine tumors seemed to inhibit colorectal tumor development in the mouse, and gender-specific effects on tumor multiplicity in the distal mouse colon and rectum mimic the situation in humans where males have a larger number of advanced adenomas and carcinomas in the distal colon and rectum than females. The mouse model of colon-preferential gene targeting described here should facilitate efforts to define novel factors and mechanisms contributing to human colon tumor pathogenesis, as well as work on tumor-promoting environmental factors and agents and strategies for cancer prevention and treatment.