The methotrexate, vinblastine, doxorubicin, cisplatin (M-VAC) regimen has been considered as standard treatment of metastatic bladder carcinoma till recent years. The superiority of M-VAC both to cisplatin alone and to another cisplatin combination regimen has been demonstrated in randomized studies. During the last years, the use of gemcitabine in metastatic bladder carcinoma has considerably increased, mainly in combination with cisplatin (CG). A phase III trial comparing M-VAC and CG demonstrated similar activity and less toxicity for CG, which has now become the new standard of care for patients with metastatic bladder carcinoma. The substitution of cisplatin with carboplatin, the combination of platinum and taxanes, and the addition of a third drug to basal CG combination represent possible ways to improve outcome. Among the novel cytotoxic compounds, pemetrexed has raised interest, since a phase II second-line study showed a 28% response rate with a manageable toxicity profile. Vinflunine is a novel antitubulin agent with a relevant clinical activity in pretreated metastatic bladder carcinoma (18% response rate, 6.6 months median survival). Novel biologic compounds (in particular drugs targeting epidermal growth factor receptor) are being tested in metastatic bladder carcinoma also and much effort is being pursued in understanding the determinants of tumor response. Crucial mutations to which the tumor becomes addicted have to be discovered so that more effective and specific drugs or combinations can be delivered.