c-Myb has been investigated in the context of the hematopoietic system where it has been shown to regulate progenitor cell expansion and differentiation of a number of lineages. The capacity to grow and expand specific blood cell lineages in vitro using well defined growth factors plus the vast range of cell surface lineage markers that identify different cell types has driven our understanding of the spectrum of roles that c-Myb plays in this tissue compartment. In addition, c-Myb is also an important transcription factor in non-hematopoietic tissues but the restricted spectrum of cell phenotyping reagents has hampered in-depth investigation. In the case of the colonic crypt the absence of phenotyping reagents of the quality employed in identifying blood cell lineages is partly compensated for by the spatial and temporal information that is inherent in the crypt structure. Using different tools to those used in the blood system we have gained insights in the multiple roles played by c-Myb in colon epithelial cells. These observations, when combined with the understanding of c-Myb action in blood cells, is providing a clearer view as to how c-Myb operates in normal cells and how this is subverted in diseases like cancer.