The effect of interferon alpha (IFNalpha2) given alone or in combination has been widely explored in clinical trials over the past 30 years. Despite the number of adjuvant studies that have been conducted, controversy remains in the oncology community regarding the role of this treatment. Recently an individual patient data (IPD) meta-analysis at longer follow-up was reported, showing a statistically significant benefit for IFN in relation to relapse-free survival, without any difference according to dosage (p = 0.2) or duration of IFN therapy (p = 0.5). Most interestingly, there was a statistically significant benefit of IFN upon overall survival (OS) that translates into an absolute benefit of at least 3% (CI 1-5%) at 5 years. Thus, both the individual trials and this meta-analysis provide evidence that adjuvant IFNalpha2 significantly reduces the risk of relapse and mortality of high-risk melanoma, albeit with a relatively small absolute improvement in survival in the overall population. We have surveyed the international literature from the meta-analysis (2006) to summarize and assimilate current biological evidence that indicates a potent impact of this molecule upon the tumor microenvironment and STAT signaling, as well as the immunological polarization of the tumor tissue in vivo. In conclusion, we argue that there is a compelling rationale for new research upon IFN, especially in the adjuvant setting where the most pronounced effects of this agent have been discovered. These efforts have already shed light upon the immunological and proinflammatory predictors of therapeutic benefit from this agent--that may allow practitioners to determine which patients may benefit from IFN therapy, and approaches that may enable us to overcome resistance or enhance the efficacy of IFN. Future efforts may well build toward patient-oriented therapy based upon the knowledge of the unique molecular features of this disease and the immune system of each melanoma patient.