The treatment of metastasized urothelial cancer has been evolving in recent years. In particular, in the second-line setting after the failure of platinum-containing therapy, options are few and besides vinflunine, the recently approved standard in Europe, well-designed highly selective clinical trials may be possible alternatives for patients in this palliative situation. However, targeted therapy approaches have not achieved the same results in urothelial cancer as for instance in renal cell carcinoma. Many of the new targeted drugs have been investigated as single agents in phase II clinical trials without convincing oncologic outcome. This review aims to highlight the most relevant clinical studies examining targeted agents in the second-line setting of metastasized transitional carcinoma of the urothelium.