Four decades of clinical and basic research have laid a solid base for clinicians to choose the best possible treatment for patients with melanoma. There has been a relative and absolute decrease in mortality despite increasing incidence. However, this decline in mortality is primarily the result of programs for primary and secondary prevention, not therapeutic advances. Conventional and high-dose immunomodulatory regimens and cytostatic therapy have failed to improve the prognosis. Whether the high-dose interferon-alpha therapy introduced by Kirkwood et al. 2001 can produce sustainable improvement in cure rate is controversial. Further developments such as treatment with recombinant cytokines (especially IL-2 and GM-CSF), specific blockade of neoplastic signal transduction and vaccination are the central issues in current research. In the future the task will be to offer an highly individualized therapy plan, based on specific prognostic and risk criteria defined in molecular genetic parameters. Indiscriminate use of newer therapeutic approaches is simply not affordable in this age of shrinking financial resources for health care.