Urothelial carcinoma of the bladder is unique among epithelial carcinomas in its divergent pathways of tumorigenesis. Low-grade papillary tumours rarely become muscle-invasive and they frequently harbour gene mutations that constitutively activate the receptor tyrosine kinase–Ras pathway. By contrast, most high-grade invasive tumours progress to life-threatening metastases and have defects in the p53 and the retinoblastoma protein pathways. Correcting pathway-specific defects represents an attractive strategy for the molecular therapy of urothelial carcinomas.