Invasive bladder cancer has a predilection for early, occult metastasis. Despite effective local control from radiotherapy or cystectomy, approximately 50% of the patients with clinically localized, invasive bladder cancer ultimately die of their disease. Over the past 25 years, systemic chemotherapy has been combined with definitive local treatment in an attempt to improve cure rates. Non-randomized phase I-II trials have shown promising results, with significant tumor down-staging. However, many randomized trials have failed to show a statistically significant survival benefit from adjunctive systemic chemotherapy. Recently, two intergroup randomized trials have shown a survival benefit from neoadjuvant combination chemotherapy, although the differences between the arms have not been dramatic. Adjuvant chemotherapy trials to date have failed to show statistically improved survival, although most published studies have been methodologically flawed. This review analyzes the results of published data and constructs a practical paradigm for patient management.