Upper tract urothelial cancer (UTUC) is an aggressive disease associated with significant morbidity and mortality. Radical nephroureterectomy (RNU) with bladder cuff removal is considered the standard of care for most invasive UTUCs but distant relapses after surgery for locally advanced, high-grade disease are common. Although multimodality treatment with perioperative chemotherapy has been investigated thoroughly in recent years, adjuvant chemotherapy has primarily been analyzed in small retrospective uncontrolled studies and a clear benefit for this treatment modality is yet to be established. It is likely that the high incidence of renal insufficiency after surgery substantially limits the applicability of adjuvant chemotherapy with cisplatin-based regimens. Neoadjuvant cisplatin-based chemotherapy has several practical advantages over adjuvant therapy, including better patient tolerance in the preoperative setting when a patient has two kidneys rather than one and the obtainment of prognostic information from pathological downstaging. Although, some academic centers have adopted neoadjuvant chemotherapy as a de facto treatment standard for patients with high-grade locally advanced UTUC, this treatment approach has not been prospectively validated or adopted in general urologic practice. A multicenter trial of neoadjuvant chemotherapy for locally advanced high-grade UTUC could further define the role of neoadjuvant chemotherapy in treating UTUC.