Genetic analysis of melanoma has allowed us to identify a population of patients who have more aggressive disease and harbor the driver mutation BRAF. This mutation is found in approximately 50% of metastatic disease and provides a target for focused therapies to control this disease. These responses are usually brisk; however, they lack the durability of immunotherapy. Frontline therapy for patients with BRAF-mutated melanoma is not as straightforward as prescribing BRAF/MEK inhibitors. Prior trials of combination immunotherapy demonstrate similar responses and durability of responses in patients with BRAF wild-type as well as BRAF-mutated disease. Decisions about immunotherapy, targeted therapy, or the combination of immunotherapy with targeted therapy require an oncologist to evaluate multiple factors to select which treatment option is best for the patient. Trials for metastatic melanoma have included biomarkers as secondary endpoints and aim to identify some way to predict a response, or lack thereof, to therapy. Here, we discuss the utility and reliability of biomarkers in determining therapy for patients with BRAF-mutated metastatic melanoma and discuss combination immunotherapy with targeted therapy versus sequential immunotherapy/targeted therapy as well as which regimen should be implemented as initial therapy.