Melanoma remains one of the most vexing problems faced by dermatologists. The incidence of melanoma is increasing faster than any other cancer in the United States,1,2 with the lifetime risk now estimated to be 1 in 59 (1 in 39 for white men).3 It is not simply a matter of earlier, more aggressive diagnosis because tumors of all thickness have shown increases in incidence. More than 68,130 new cases of invasive melanoma are expected to be diagnosed this year.4 It is now the sixth most common cancer in the United States and is presently the leading cause of cancer deaths in women between the ages of 20 and 35.5 Fortunately there is also some good news about melanoma. There have been significant advances recently in our ability to identify patients at high risk, to diagnose melanoma at an earlier and more curable point in the disease process, and to treat melanoma of all stages. Now more than 85% of newly diagnosed melanoma patients have the disease limited to the primary cutaneous site (American Joint Committee on Cancer stage I and II) and have an excellent prognosis. The ability to sequence and analyze the human genome has altered our traditional dysplastic nevus to melanoma model and identified multiple divergent oncogenic pathways leading to melanoma. This new information is having a significant impact on both bench research and clinical trials and, as medicine becomes more personalized, will likely help create more customized and targeted therapy. In addition, there are new noninvasive technologies developed each year that help clinicians evaluate suspicious lesions. As experience with dermoscopy increases, so too does the ability to recognize patterns more clearly and an associated increase in the sensitivity and specificity of diagnosing pigmented lesions. This helps reduce the number of unnecessary biopsies as well as minimize the risk of missing potentially serious lesions. In addition, bedside confocal microscopy, optical coherence tomography, reflex transmission imaging, and other imaging systems, such as SIAscopy and MelaFind, have shown real potential to improve our ability to quickly and accurately determine a pigmented lesion’s malignant potential. Sentinel lymph node biopsies have been shown to accurately stage regional lymph node basins in stage I and II melanoma patients, and as histologic examination of the biopsied nodes become more sensitive and more thorough, our ability to define true positive and negative subsets will be even further enhanced. In this issue of the journal we will examine many of the aspects of melanoma and discuss where the experts in our field believe we stand in 2011 and where we may be headed in the future. We begin with an in-depth look at the epidemiology of melanoma. Dr Darrel Rigel discusses the alarming increase in both the incidence and mortality of melanoma and evaluates the exogenous and endogenous risk factors that may help us identify those at higher risk for the disease and potential avenues to reduce their risk. This article is followed by a review of the latest discoveries on the divergent pathways of melanoma development from Drs Velez, Ko, and Tsao. New mutations have been identified that may have significant practical implications in patient care. Drs Wasserman and Monheit present an update on the most recent bedside technology available to help clinicians diagnose melanoma. Dr Marghoob and colleagues continue in the next article with an in-depth discussion on dermoscopy of pigmented lesions and other tumors with particular attention to the pediatric population. Dr Merrik Ross, a surgical oncologist from the M D Anderson Cancer Center, presents an update on sentinel node biopsies and its implications in clinical practice after 20 years of experience. Dr Jose Lutzky, a medical oncologist from Mount Sinai, addresses new therapeutic options in the medical management of advanced melanoma. Dr Marc Brown sums up the material and details a practical clinical approach to the melanoma patient. Likewise, Dr Eric Parlette discusses melanoma in situ and a practical approach to treatment. We are indebted to these thought leaders in our field for sharing their experience with us.