Immune checkpoint blockade has revolutionized the treatment of multiple tumor types, including melanoma and nonmelanoma skin cancers. The use of immune checkpoint blockade is curtailed by tissue toxicities termed immune-related adverse events (irAEs), which occur most quickly and most often in the skin. We review the rationale for immune checkpoint blockade use, current agents, use in skin cancers, autoimmune manifestations in the skin, and considerations for predictive biomarkers and treatment options on the basis of skin pathogenesis. We also highlight major gaps in the field and the lack of preclinical modeling in the skin. A deeper understanding of irAE pathophysiology may help to uncouple toxicity and efficacy but mandates an interdisciplinary approach, including foundational skin immunology and autoimmune pathogenesis.