Radical surgery alone for high-risk upper-tract urothelial carcinoma (UTUC) is often inadequate for long-term cancer control. Numerous studies implicate failure presumably attributable to metastatic disease. Therefore, multimodal therapy by way of perioperative chemotherapy is integral to improve cancer outcomes and disease-specific survival. Despite this apparent reality, there is lack of consensus regarding which patients will need additional therapy, optimal timing for delivery of agents, and specific regimens to be utilized. Progress is being made, however, to explore these issues both by extrapolation from the bladder cancer literature as well as studying outcomes from retrospective UTUC series. Prospectively accruing studies for both neoadjuvant and adjuvant chemotherapy will likely mature in the next 5 years thereby providing higher level data to better guide standard of care.