Conventional first-line platinum-based combination chemotherapy with gemcitabine/cisplatin and standard or dose-dense methotrexate, vinblastine, doxorubicin and cisplatin yields high response rates but suboptimal long-term outcomes for advanced urothelial cancer. Salvage therapy is an unmet need, with disappointing outcomes. The emergence of novel biological agents offers the promise of improved outcomes. Neoadjuvant therapy preceding cystectomy for muscle-invasive bladder cancer provides an important paradigm and an interesting approach in developing novel agents. Patients who are not candidates for cisplatin require special attention. A multidisciplinary approach and collaboration among laboratory scientists, oncologists, urologists and radiation oncologists is necessary to make therapeutic advances. Recent and ongoing trials of novel chemotherapeutic and biological agents are reviewed.