Advanced bladder/urothelial cancer remains an incurable terminal disease, and accounts for 3% of the cancer related mortality in the United States. Systemic chemotherapy achieves palliation, survival benefit, and occasional long-term remissions. The two regimens that have been widely adopted consist of either cisplatin and gemcitabine, or the MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) regimen. Novel therapies are being evaluated in metastatic bladder cancer to improve survival outcomes. A randomized trial of larotaxel (a novel taxane) and cisplatin vs cisplatin and gemcitabine in frontline therapy of metastatic urothelial cancer is ongoing. The studies evaluating therapies targeted frontline involve cisplatin and gemcitabine with or without cetuximab (ongoing), and with or without bevacizumab (CALGB proposed trial). With the advent of adjuvant/neoadjuvant cisplatin-based therapy, and improvement in supportive care, more patients are being considered for second-line therapies in urothelial cancer thus making this a field of emerging importance. The only phase III trial in pretreated urothelial cancer compared vinflunine with best supportive care, and revealed no significant survival improvement. Clinical trials are ongoing with pazopanib, a VEGF inhibitor, and Zactima, a VEGF and EGFR inhibitor. The biggest hurdle to progress in advanced bladder cancer has been the slow accrual to studies in the United States. Making clinical trial participation a priority in bladder cancer is the dire need of the moment. At the same time, it is essential to take into account the changing needs of the population afflicted with bladder cancer, and tailor the therapeutic trials to fit a contemporary patient.