Deciphering the complex mechanisms of intestinal epithelial development will require multiple cell and molecular approaches in both in vitro and whole animal systems. Additionally, the use of model organisms such as D. melanogaster, C. elegans, and zebrafish will help describe paradigms that may be investigated in mammals as well as serve as test systems for findings from mammals. This manuscript reviewed only one approach to understanding intestinal development. However, the Cdx story and the information to be mined from an understanding of SI gene transcription is not at an end. As the other pieces of the transcriptional puzzle of the SI gene are assembled there will be new information to generate hypotheses on the relationship of transcriptional mechanisms to cancer pathogenesis.