The overall survival of advanced melanoma has improved dramatically. Immunotherapies, specifically checkpoint inhibitors, have played a large role in this improvement. These agents have also shown benefit in the adjuvant setting, are approved for treatment of resected stage II, III, and IV melanoma, and play an evolving role in the neoadjuvant setting. Although generally well tolerated, immune-related adverse events occur and can be severe. Here we focus on some severe and potentially long term toxicities, including cardiovascular and neurologic toxicities. Our understanding of the acute and long-term toxicities of immune checkpoint inhibitors continues to evolve. Oncologists must continue to balance cancer risk and treatment-related toxicities.