Urothelial cell carcinoma (UCC) of the bladder is the fifth most common cancer worldwide and is associated with activating mutations in FGFR3. Ahmad et al. now report a mouse model that conditionally expresses an activating mutation in Fgfr3 in the urothelium. This mutation alone is not sufficient to initiate UCC, but it can cooperate with other oncogenes to cause tumours in other tissues. The data also indicate that appropriate expression of feedback inhibitors of FGF signalling, such as Sprouty2, might act like a tumour suppressor to prevent UCC in healthy individuals.