Strong focus on understanding the cellular and molecular biology of melanoma and the role of anti-tumour immunity in melanoma have generated unprecedented therapeutic opportunities in the disease. Over 60% of melanomas have mutations that activate the RAS/RAF/MEK/ERK pathway that has led to identification of systemic therapies that improve overall survival in the advanced disease setting, and potentially offer even more significant impact in the adjuvant setting. We have recently showed that primary melanomas without mutations in these driving oncogenes have extraordinarily high numbers of sequence variants consistent with chronic UV damage. These melanomas harbor multiple potential drivers suggesting single agent therapies will be of limited value. We propose the greatest potential to reduce mortality from melanoma, a disease characterised by the development of metastases from small primary tumours, is the combination of systemic therapies particularly in the adjuvant setting. The new systemic therapies for melanoma coupled with ongoing understanding of the biology of the disease is poised to further accelerate novel therapeutic opportunities.