Answer questions and earn CME/CNE Although overall cancer incidence rates are decreasing, melanoma incidence rates continue to increase about 3% annually. Melanoma is a significant public health problem that exacts a substantial financial burden. Years of potential life lost from melanoma deaths contribute to the social, economic, and human toll of this disease. However, most cases are potentially preventable. Research has clearly established that exposure to ultraviolet radiation increases melanoma risk. Unprecedented antitumor activity and evolving survival benefit from novel targeted therapies and immunotherapies are now available for patients with unresectable and/or metastatic melanoma. Still, prevention (minimizing sun exposure that may result in tanned or sunburned skin and avoiding indoor tanning) and early detection (identifying lesions before they become invasive or at an earlier stage) have significant potential to reduce melanoma incidence and melanoma-associated deaths. This article reviews the state of the science on prevention and early detection of melanoma and current areas of scientific uncertainty and ongoing debate. The US Surgeon General's Call to Action to Prevent Skin Cancer and US Preventive Services Task Force reviews on skin cancer have propelled a national discussion on melanoma prevention and screening that makes this an extraordinary and exciting time for diverse disciplines in multiple sectors-health care, government, education, business, advocacy, and community-to coordinate efforts and leverage existing knowledge to make major strides in reducing the public health burden of melanoma in the United States. CA Cancer J Clin 2016;66:460-480. © 2016 American Cancer Society.