Abstract Cancer immunotherapies utilizing immune checkpoint inhibitors (ICI) have demonstrated durable efficacy in a proportion of patients with advanced/metastatic cancers. More recently, the use of ICIs for the adjuvant treatment of patients with surgically resectable melanoma has also demonstrated efficacy by improving relapse-free survival and in the case of ipilimumab (anti–CTLA-4) also improving overall survival. Although promising, the effective scheduling of surgery and immunotherapy and its duration is not well elucidated. Recent preclinical studies suggest that surgery followed by adjuvant therapy might be suboptimal as compared with an approach in which immunotherapy is applied before surgery (neoadjuvant immunotherapy). Encouraging findings from early-phase clinical trials in melanoma, non–small cell lung carcinoma, and glioblastoma support the idea that neoadjuvant immunotherapy might have improved clinical efficacy over an adjuvant application. In this review, we discuss the existing rationale for the use of neoadjuvant immunotherapy, its apparent strengths and weaknesses, and implications for the design of future clinical trials.