Decades of investment in the cellular and molecular biology of melanoma and the role of the immune system in cancer have generated a number of exciting targets in melanoma.  Two thirds of melanomas have mutations that activate the RAS/RAF/MEK/ERK pathway that has led to systemic therapies that improve overall survival in the advanced disease setting, and potentially offer even more significant impact in the adjuvant setting. In parallel a number immunological targets have been identified that can be modulated by therapeutic antibodies to activate an anti-tumour immune response.  The CTLA4-inhibitory antibody ipilimumab can improve overall survival in the advanced disease setting and results from the first adjuvant trials will be available in 2013.  Perhaps the greatest promise to impact mortality from melanoma, a disease characterized by the development of metastases from small primary tumours, is the combination of systemic therapies.  The new systemic therapies from melanoma are fundamentally changing the clinical management of melanoma with recent advances in the cellular and molecular biology of melanoma poised to further accelerate this paradigm shift.