Classic interferon-alpha formulations have antitumour activity in a variety of neoplastic diseases, including the adjuvant and palliative setting of metastatic melanoma, as single agents or in combination with chemotherapy and/or interleukin-2. Pegylated interferon, widely used for the treatment of hepatitis, seems to be at least equally efficacious as standard recombinant interferon in the treatment of metastatic melanoma, and the available evidence suggests that equi-efficacious doses have somewhat lower acute toxicity. Moreover, the favourable pharmacokinetic properties of pegylated interferon allow the administration on a weekly basis, with sustained exposure to interferon during that entire period. Several clinical trials have been conducted testing adjuvant and palliative treatment with pegylated interferon-alpha in high-risk melanoma patients with promising results. The role of pegylated interferons in the setting of advanced metastatic melanoma will need further investigation in clinical trials, potentially in combination with targeted or cytotoxic agents with regard to synergistic antiangiogenic and cytotoxic effects. The use of pegylated interferons in earlier stage melanomas will be investigated in upcoming trials.