Immune checkpoint blockade has demonstrated success in treating cancer but can lead to immune-related adverse events (irAEs), illustrating the centrality of these pathways in tolerance. Here, we describe programmed cell death protein 1 (PD-1) control of T cell responses, focusing on its unique restraint of regulatory T cell function. We examine successes and limitations of checkpoint blockade immunotherapy and review clinical and mechanistic features of irAEs. Last, we discuss strategies to modulate PD-1 blockade to enhance antitumor immunity while limiting autoimmunity.