High dose interferon-α (HD IFN) is approved by the United States Food and Drug Administration for adjuvant treatment of patients with stage III melanoma after complete surgical resection. Despite this, clinicians and patients around the world and in many parts of the US have failed to embrace this treatment option because of the lack of overall survival benefit and minimal other clinical benefits seen in randomized trials, combined with the therapy's substantial toxicity. This article reviews the data from the randomized trials that lead to this conclusion and discuss why arguments often advanced in favor of using HD IFN are not persuasive. New treatment options are needed for adjuvant therapy of melanoma. In the meantime, the data from the randomized trials make it difficult for many clinicians and patients to have enthusiasm for adjuvant HD IFN.