Given the recent expansion of treatment options in advanced melanoma, oncologists now have the opportunity to choose among multiple effective and fairly well-tolerated treatment options. The appropriate sequence and combination of targeted agents and immunotherapy are currently under investigation. Guidelines are evolving rapidly in both the adjuvant and metastatic settings with the accumulation of clinical experience and new trial outcomes. A 49-year-old man initially diagnosed in 1995 with cutaneous melanoma presented to the authors’ care in 2009 with metastatic, BRAF V600E–mutant melanoma. His treatment course to date has included surgery, adjuvant radiotherapy, and interferon, metastasectomies, granulocyte-macrophage colony-stimulating factors, a clinical trial with the BRAF inhibitor (BRAFi) vemurafenib (PLX-4032), clinical trial with combination BRAF plus MEK inhibition with vemurafenib plus GDC-0973, and combination targeted and immune therapy with vemurafenib plus the anti-CTLA4 antibody ipilimumab. This case report illustrates the long-term management of a patient with metastatic melanoma using targeted and immune therapy, evolution in treatment guidelines, next directions in research, and the critical role of clinical trials in advancement of patient care.