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Neoadjuvant cisplatin-based chemotherapy is standard treatment for muscle-invasive bladder cancer before radical cystectomy (RC). Despite level 1 evidence demonstrating an overall survival benefit for patients undergoing RC after neoadjuvant chemotherapy (NAC), acceptance rates are still low. In high-risk upper tract urothelial cancer (UTUC), cumulative evidence suggests that NAC for locally advanced UTUC can improve oncological outcome. Ongoing phase 3 trials will finally prove the benefit or futility of NAC in this tumor entity. Since urothelial cancer (UC) is a heterogeneous disease, predictive biomarkers are needed to select specific patient populations and potentially increase response rates to NAC. Novel targeting therapies, including immune checkpoint inhibitors, have been approved for metastatic UC. In combination with predictive biomarkers, these might have the potential to change systemic therapy for UC from a “one-fits-all” principle to a more individualized approach.