The global incidence of melanoma is increasing, and the prognosis for patients remains poor. High-dose interferon-alpha (HD-IFN-a) and pegylated IFN are the only US Food and Drug Administration (FDA)-approved agents for adjuvant therapy for high-risk melanoma, and an improvement in relapse-free survival (RFS) has been observed consistently across nearly all published studies and meta-analyses. Some studies and meta-analyses have also supported an overall survival (OS) benefit. However, despite a number of adjuvant studies, controversy remains regarding the role of this treatment. As the benefits in OS are modest with IFN treatment, there is therefore a need for new therapeutic targets, new drugs, and optimum patient selection. Current research is investigating new adjuvant agents, either individually or in combination, which may advance the standard of care beyond HD-IFN. Additionally, identifying biomarkers of patients with greater likelihood of response may allow patient-specific therapeutic approaches. Following the recent FDA approval of ipilimumab, vemurafenib, dabrafenib, and trametenib for metastatic melanoma, ongoing adjuvant trials are now underway.