A 40-year-old man with stage III melanoma arising from his left shoulder underwent wide local excision, sentinel lymph node biopsy, and lymph node dissection. Nine months after receiving adjuvant biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2 (IL-2), and interferon alfa as part of a clinical trial, he developed headaches and right-hand weakness and was found to have a 2-cm left parietal CNS metastasis. A comprehensive staging workup identified multiple nonspecific subcentimeter pulmonary nodules. The brain mass was resected and confirmed to be metastatic melanoma; the surgical bed was treated with stereotactic radiosurgery. He was monitored off therapy, but 5 months later, he developed a second left parietal CNS metastasis and enlarging lung nodules. The new brain lesion was treated with stereotactic radiosurgery, and he began systemic therapy with ipilimumab on a clinical trial. After the third dose, he presented with headache, nausea, and vomiting; a brain magnetic resonance imaging scan showed left anterior temporal enhancement, possibly representing new disease. His symptoms improved with a course of corticosteroids. Restaging of the chest showed a mixed response among the pulmonary nodules. After tapering off corticosteroids, he received the fourth dose of ipilimumab, which was complicated by grade 3 transaminitis and hypophysitis with documented hypothyroidism and adrenal insufficiency. They were managed with corticosteroids and thyroid and adrenal hormone replacement. Restaging scans showed further disease regression except for new confluent enhancing nodules and edema in the left temporal lobe. Craniotomy and resection of this area showed only necrotic tissue with no viable melanoma cells. Nine years after treatment with ipilimumab, he is alive and shows no evidence of melanoma on the basis of annual computed tomography scans of the chest, abdomen, and pelvis and magnetic resonance imaging scans of the brain. He has full neurologic function but still requires hormone replacement for persistent hypopituitarism.