Background: Radical cystectomy is the standard of care for patients with localized muscle-invasive bladder cancer; however, 50% of patients still relapse in distant sites following surgery. A systemic approach is needed to improve outcomes in bladder cancer in the metastatic and perioperative settings. Methods: We reviewed the literature for use of systemic chemotherapy in bladder cancer and its role in metastatic, neoadjuvant, and adjuvant settings, including patients with comorbidities and renal dysfunction. Current controversies on the role of chemotherapy in neoadjuvant and adjuvant settings as well as the role of novel agents are discussed. Results: First-line cisplatin-based polychemotherapy improves survival in the metastatic setting and is the standard of care. Approved regimens for subsequent-line therapy do not exist. Chemotherapy has a modest benefit in the neoadjuvant setting, but evidence is insufficient to justify its role in the adjuvant setting despite a possible benefit. Carboplatin cannot be substituted for cisplatin in fit patients, and the addition of taxane to a standard regimen cannot be recommended. Conclusions: Systemic chemotherapy plays a central role in the management of invasive bladder cancer in the metastatic and neoadjuvant settings, but its role in the adjuvant setting remains undefined. Neoadjuvant chemotherapy is underutilized and should be routinely used. Pathological downstaging strongly correlates with improved outcomes and may serve as a surrogate end point for survival. An urgent need exists for the development of novel therapeutic agents to improve outcomes.