Transitional cell carcinoma of the bladder is a common malignancy worldwide that is associated with significant morbidity and mortality. Although superficial tumors can often be treated effectively, invasive cancers not only require invasive surgery, but are also refractory to aggressive chemotherapy and radiotherapy. In this issue of Genes & Development, Puzio-Kuter and colleagues (pp. 675-680) describe an elegant genetically engineered murine model of bladder cancer that recapitulates many of the cardinal features of the human disease. The development of such models together with the application of new approaches to enumerate the complement of genetic alterations in bladder will provide new insights into the molecular nature of this disease. Moreover, the anatomy of this urinary malignancy provides a unique opportunity for innovative translational studies.