Abstract Colorectal cancer, one of the most common human malignancies in the Western world, is often subdivided based on tumor location in either the distal or proximal colon. Several mouse models have been developed to study human colorectal cancer, but few display this clear distinction between the two colonic locations. By crossing ApcMin/+ and Smad3 mutant mice, we showed that combined activation of the Wnt pathway and attenuation of the transforming growth factor-β (TGF-β) pathway causes high multiplicity and rapid onset of invasive tumorigenesis almost exclusively in the distal colon, closely mimicking the familial adenomatous polyposis (FAP) disease and consisting with distinct colorectal cancer etiologies based on tumor location. Transcriptional profiling revealed higher expression of several TGF-β activators in the normal distal mucosa than in proximal mucosa, suggesting a stronger reliance on TGF-β-mediated growth control in the distal than in the proximal colon. ApcMin/+Smad3−/− mice provide an alternative model to ApcMin/+ mice to study FAP and distal sporadic colorectal cancer. This model will be useful in dissecting mechanistic and etiologic differences between proximal and distal colonic cancer, whereas the confinement of tumorigenesis to the distal colon offers unique advantages in monitoring tumor progression by in vivo imaging. (Cancer Res 2006; 66(17): 8430-8)