The explosion in novel cancer immunotherapies has resulted in extraordinary clinical successes in the treatment of multiple cancers. Checkpoint inhibitors (CPIs) that target negative regulatory molecules have become standard of care. However, with the growing use of CPIs, alone or in combination with chemotherapy, targeted therapies, or other immune modulators, a significant increase in immune-related adverse events (irAEs) has emerged. The wide-ranging and currently unpredictable spectrum of CPI-induced irAEs can lead to profound pathology and, in some cases, death. Growing evidence indicates that many irAEs are a consequence of a breakdown in self-tolerance, but the influence of genetics, the environment, and the mechanisms involved remains unclear. This review explores key questions in this emerging field, summarizing preclinical and clinical experiences with this new generation of cancer drugs, the growing understanding of the role of the immune response in mediating these toxicities, the relationship of CPI-induced autoimmunity to conventional autoimmune diseases, and insights into the mechanism of irAE development and treatment.