The U.S. Food and Drug Administration has approved pembrolizumab for patients with resectable locally advanced head and neck squamous cell carcinoma expressing PD-L1 (CPS ≥1). This marks the first approval of a checkpoint inhibitor in the perioperative setting, based on the phase 3 KEYNOTE-689 trial showing improved event-free survival and tumor shrinkage with perioperative administration. Dana-Farber Cancer Institute investigators led the trial. The approval represents a paradigm shift in head and neck cancer treatment workflows.