Administration of neoadjuvant chemotherapy preceding radical cystectomy in patients with bladder cancer remains a matter of debate. Results of prospective, randomized studies have demonstrated an overall absolute survival benefit of 5% at 5 years, provided cisplatin-based combination regimens are used. Owing to the perception of a modest survival benefit, the medical community has been slow to adopt the use of neoadjuvant chemotherapy. Other reasons for the underuse of neoadjuvant chemotherapy range from patient ineligibility to fear of delaying potentially curative surgery in nonresponders. Instead, several institutions have adopted an individualized, risk-adapted approach, in which the decision to administer chemotherapy is based on clinical stage and patient comorbidity profile. The development of new cytotoxic and targeted therapies, in particular immune checkpoint inhibitors, warrants well-designed prospective studies to test their efficacy alone or in combination in the neoadjuvant setting. Moving forward, genomic characterization of muscle-invasive bladder cancer could offer information that aids clinicians in selecting the appropriate chemotherapy regimen. Following neoadjuvant therapy, every effort should be made to ensure optimal surgery, as surgical margins and the number of removed lymph nodes are prognostic factors; thus, radical cystectomy and a meticulous extended pelvic lymph node dissection should be performed by expert surgeons.