Strategies for altering constitutional or somatic genotype in mice are well established, but approaches to generate mosaic genotypes in mouse tissues are limited. We showed that a functionally inactive Cre recombinase transgene with a long mononucleotide tract altering the reading frame was stochastically activated in the mouse intestinal tract. We demonstrated the utility of this approach by inducing colonic polyposis after Cre-mediated bi-allelic inactivation of the Apc gene.