For the first time, the cell type to give rise to invasive urothelial carcinoma was pinpointed in our recetnly published study in Nature Cell Biology (Shin, Beachy NCB 2014). In this study, we showed two lines of evidence indicating that the bladder stem cells are solely responsible for tumorigenesis. When we mark the bladder stem cells, the tumors are also marked. When we remove, or ablate, the stem cells, no tumors arise after carcinogen treatment. Furthermore, we addressed the question of whether bladder cancers arise as the result of genetic changes to one or more of these bladder stem cells. To do so, we used a genetically engineered mouse with cells that fluoresce green, but which can be triggered to randomly fluoresce one of three other colors: red, blue or yellow. Known as a “rainbow mouse,” the animal allowed us to more precisely determine the origin of groups of cells. If all cells in a tumor are red, for example, it is much more likely that they originated from a single cell. Our observation that a single marked cell under mutagenic pressure can aggressively proliferate and spread through extensive contiguous regions of the urothelium provides a clear basis for the clonal relationships identified among multifocal tumors within a single bladder. This aggressive intraepithelial expansion of a single clone and our observations of invasive tumors surrounded by non-invasive regions of clonally related carcinome in situ urothelium also provide a correlate for the commonly reported occurrence of a tumor surrounded by a region of abnormal but benign epithelium.