Invasive transitional cell bladder cancer is associated with occult metastasis. Approximately 50% of patients with clinically localized, invasive bladder cancer ultimately die of their disease. Systemic chemotherapy has been combined with radical cystectomy in an attempt to improve survival. Phase I and II trials have achieved tumor down-staging. Initial randomized trials did not show a statistically significant survival benefit from systemic single agent chemotherapy. More recently, two multi-center randomized trials have shown a significant survival benefit from neoadjuvant combination chemotherapy. Adjuvant chemotherapy trials, to date, have failed to show statistically improved survival, although most published studies have been methodologically flawed. For invasive, clinically nonmetastatic bladder cancer, neo-adjuvant chemotherapy followed by radical cystectomy is one of the new standards of care. The role of postsurgical systemic chemotherapy appears promising, but has not been proven in a randomized trial. Molecular prognostication is now being incorporated into the design of clinical trials of adjuvant chemotherapy for bladder cancer.