In the past few years, there has been an explosion of new data on efficacious targeted and immunotherapeutic approaches for the management of malignant melanoma. Multiple treatment options currently exist with potential for clinical benefit and improvement in outcomes for melanoma patients, creating the need to fully comprehend the advantages and disadvantages of the different approaches, appropriate patient subsets that benefit from therapy, optimal combinations and sequence of therapies, and integration of evidence-based strategies into traditional modalities. As new clinical findings emerge in melanoma management, several thought-provoking issues challenge the community oncologists’ perspectives in the optimal utilization of multidisciplinary approaches to treatment of the different stages of the disease. In this video discussion, Drs. John M. Kirkwood and Antoni Ribas summarize the key take-home messages on the latest advances in melanoma research presented during the Annual Great Debates and Updates in Melanoma 2014 meeting held in Phoenix, Arizona.