Interferon-alpha (IFNalpha) is a pleiotropic cytokine with various direct and indirect inflammatory response modulating activities. Some of these activities may have direct or indirect antitumour effects. For such a wide range of biological activities, the dose for optimal biological activity may differ greatly from the maximally tolerated dose as different effects are mediated by different concentrations of IFNalpha. Because of its immunomodulatory effects, it has been extensively studied in melanoma patients. Little antitumour activity has been demonstrated in metastatic stage IV melanoma, with overall response rates of 10-15%, which were not dose-related. Yet, IFNalpha has been widely studied in the adjuvant setting for stage II and III disease. Many trials have been underpowered, have used very heterogeneously mixed patient populations, a wide variety of doses and treatment schedules, and have suffered from early and unplanned analyses. Mature data are still pending in some 3000 patients of the overall approximately 6000 patients that participated in the adjuvant trials. A meta-analysis has demonstrated a similar impact on relapse-free survival across various dose ranges of IFNalpha, but no significant impact on overall survival (OS). In light of the lack of impact on OS and the considerable to serious dose-dependent toxicity of IFNalpha, we do not have a clearly dose- and schedule-defined role for IFNalpha in the adjuvant setting and have no evidence for a benefit of IFNalpha in stage IV melanoma. For the adjuvant setting, the main question: efficacy of very toxic high dose therapy versus efficacy of non-toxic long-term treatment will be answered by the mature data from the large US-Intergroup high-dose and EORTC intermediate-dose and long-term maintenance therapy trials.