A 51-year-old man presented to the dermatology clinic with an approximately 36-month history of growth of multiple skin tumors and a 6-month history of weight loss and abdominal pain. On physical examination, the patient was cachectic. There were large masses in the axillae and inguinal regions and on the abdominal wall (Panel A). Computed tomography (CT) of the whole body and magnetic resonance imaging of the head revealed metastases throughout the body. Biopsy of a chest-wall mass revealed metastatic melanoma. Treatment with one cycle of ipilimumab and nivolumab was initiated. After mutational analysis of the mass revealed a BRAF V600E mutation, the treatment was changed to dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor). Within 2 weeks after initiation of the targeted therapy, the masses started to decrease in size (Panel B). After 6 weeks of targeted therapy, a whole-body CT scan showed regression of all the metastases except for a nonresponsive metastasis in the right axilla that was surgically removed. After 12 weeks of targeted therapy, the masses had become even smaller (Panel C). In patients with melanoma, immunotherapy and targeted therapy can lead to a rapid and clinically significant tumor response. Fifteen months after the patient’s initial presentation, he was transitioned to hospice care owing to progression of disease.