Systemic chemotherapy has reached a therapeutic plateau in the treatment of transitional cell carcinomas of the urothelium. Since the advent of the combination of methotrexate, vinblastine, adriamycin and cisplatin (MVAC) in the 1980s, no chemotherapy regimen has been proven to be superior to this therapy. Only one regimen, a combination of gemcitabine and cisplatin, has been equivalent. With a similar response rate and survival, plus the benefit of an improved toxicity profile, the gemcitabine cisplatin combination has largely supplanted MVAC in physician's practices. Although a recent dose-intense version of MVAC has shown an improved toxicity profile compared with traditional MVAC, it is clear that, for many patients, a full-dose cisplatin-based chemotherapy regimen may not be a tolerable option. Tobacco use, which is a common risk factor predisposing for the development of transitional cell carcinoma, may also cause morbidities that preclude treatment with aggressive combination therapy. Therefore, there is a clear need for regimens with improved toxicity, especially for the frequently frail or elderly patient population with poor renal function. There is an additional unmet requirement in rare bladder tumors, for which treatment has traditionally been based upon anecdotal evidence, limited by small patient numbers. Currently, there is newfound hope for all bladder cancer patients, with investigators studying new combinations and novel treatment paradigms, with recent studies focusing on frail, or 'cisplatin-unfit', patients and additional studies in the setting of rare small cell or urachal carcinoma patients.