The treatment for malignant melanoma has undergone significant changes over the past few decades, with biological therapy playing an increasingly important role and replacing the traditional cytotoxic agents as the first-line therapy for this disease, both in advanced disease and adjuvant settings. Despite the developments of new modalities of therapy for melanoma, the outcome for patients with advanced disease remains poor. This article discusses the clinical studies that have shaped our current management of melanoma, both in the adjuvant setting, and in the metastatic setting. Additionally, successes and failures of clinical trials will be discussed, as they will guide the strategic development of future studies in the management of this aggressive disease.