Systemic treatment of urothelial carcinoma of the bladder requires complex approaches and is constantly evolving. Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy remains the current standard of care for muscle-invasive advanced bladder cancer. For patients ineligible for cisplatin, adjuvant treatment with nivolumab is recommended. Innovative perioperative combinations could transform the treatment landscape in the future. First-line treatment for metastatic urothelial carcinoma has long been dominated by platinum-based combinations, recently followed by the immune checkpoint inhibitor avelumab as maintenance therapy; however, recent results on the use of enfortumab vedotin and pembrolizumab in the first-line setting are expected to fundamentally change the treatment options. In subsequent lines of treatment, the not yet approved erdafitinib, as the first targeted therapy for advanced urothelial carcinoma, offers an important alternative and underscores the need for molecular testing.