Objective: The regulation of tissue development and subsequent tissue homeostasis is partly achieved through the orchestration of transcription factor expression and gene activation within stem and progenitor cell populations. Transcription factor c-Myb has emerged as a key regulator of stem/progenitor cells within multiple tissue compartments such as the gastrointestinal tract (GI), mammary gland, adult brain and epidermis. Our objective has to understand how Myb co-operates with other transcription factors and their consequent regulation of stem cell genes. Materials and Methods: We have achieved this be combining in vitro assays, radiation challenges and a unique set of mouse models exploitation of global and tissue specific knock-outs and hypomorphic mutants. Our focus has been on stem cell gene expression and the effects on tissue homeostasis and tumorigenesis. Results: In the case of the mammary gland we have now shown that Myb is required for normal and timely development and its ablation can eliminate mammary tumor formation (1). In the brain adult neurogenesis is profoundly blocked (2) while in the GI crypt development is impeded leading initially biased goblet cell development and then crypt loss (3). We then focused on the GI where the Wnt target gene, Lgr5 (leucinerich- repeat-containing G-protein-coupled receptor 5) is expressed. Along with it being an important GI stem cell marker it is also expressed in colon cancer cells and identifies cells capable of forming crypt-villus like structures in culture from single sorted (Lgr5+ve) cells. Based on co-incidental expression of lgr5 and c-myb in the GI, we investigated whether lgr5 is a c-Myb target gene. Using both in vitro and in vivo mouse models, we show that the proto-oncogene c-Myb in combination with β-catenin, is bound to and is a more potent regulator of the murine lgr5 promoter in the presence of activated β-catenin (4). Using an inducible c-Myb transgenic model we have further identified the regulation of CyclinE1 and Bmi1 as key GI stem cell genes that are controlled by c-Myb. Conclusion: These data indicate that the Wnt pathway through β-catenin converge with c-Myb in regulating lgr5 expression in the GI and more broadly in other epithelial tissues with the capacity to affect tumorigenesis.