Melanoma the deadliest form of skin cancer is an aggressive disease that is rising in incidence. treatment. In addition we review benefits and limitations of current therapies and look ahead to continued progress in melanoma prevention and therapy. Remarkable achievements in the field have already produced a paradigm shift in melanoma treatment – metastatic melanoma once considered incurable can now be treated with potentially curative rather than palliative intent. Melanoma is among the most aggressive and treatment-resistant human cancers. In 2014 an estimated 76 100 new cases and 9 710 deaths are expected in the United States with melanoma accounting for 75% of all skin cancer deaths (1). Although these stark numbers highlight the need for improved prevention strategies and treatments the explosion of discovery and concrete clinical advances in the melanoma field have brought great optimism in recent years. From identification of cancer genes to successes of new drugs in clinical trials progress in understanding melanoma is now leading the way for other malignancies. Cells of origin: melanocytes Melanomas arise from malignant transformation of melanocytes the melanin-producing cells of the skin eye mucosal epithelia and meninges that are responsible for pigmentation and photoprotection. Several common subtypes of melanoma are shown in Figure 1. Melanocytes are derived from neural crest progenitors and their development is modulated by the receptor tyrosine kinase (RTK) c-KIT and microphthalmia-associated transcription factor (MITF) (2). Fig. 1 Clinical images of melanomas. Subtypes of melanoma include superficial spreading melanoma (A) amelanotic melanoma (B) nodular YC-1 melanoma (C) acral lentiginous melanoma (D) and uveal melanoma (E). Images courtesy of H. Tsao C.H. Won and I. Kim. YC-1 Melanocytes produce two main types of pigment: brown/black eumelanin and red pheomelanin. Eumelanin is the photoprotective pigment that provides ultraviolet radiation (UVR) attenuation. Pigment synthesis is stimulated by binding of α-melanocyte stimulating hormone (α-MSH) to melanocortin 1 receptor (MC1R) on melanocytes (Figure 2). MC1R activates cAMP production and CREB-mediated transcriptional activation of MITF. MITF in turn promotes transcription of pigment synthesis genes and melanin production. MC1R is a major determinant of pigmentation and loss-of-function polymorphisms result in impaired eumelanin production with the most TNF-alpha severe loss-of-function alleles producing red hair and fair skin (2). In addition to basal pigmentation acquired pigmentation can be elicited by stimuli such as UVR (Figure 4) (3). Fig. 2 Signaling pathways in melanoma. MAPK signaling promotes cell growth and survival and is constitutively active in most melanomas. RAS family members are activated by RTKs and signal through effector proteins including PI3K RAF kinases and Ral-GEFs. Oncogenic … Fig. 4 Cutaneous response to UVR. Tanning involves p53 activation in keratinocytes in response to UVR-induced DNA damage leading to p53-mediated upregulation of proopiomelanocortin (POMC). Post-translational cleavage of POMC produces β-endorphin and … Melanoma risk factors The strongest melanoma risk factors are family history multiple moles fair skin immunosuppression and UVR. Epidemiologic studies have implicated intense intermittent UVR exposure and severe sunburns YC-1 during childhood in conferring the highest risk (4). Indoor artificial tanning devices that deliver UVR to the skin have also been linked to dose-dependent melanoma risk (5). UVR has YC-1 multiple effects in the skin including genetic changes induction of reactive oxygen species (ROS) alterations in cutaneous immune function and production of growth factors (reviewed in (6)). Recent mouse model studies YC-1 have shown that UVR induces inflammatory responses involving macrophages and neutrophils that can promote melanocytic cell survival immunoevasion and perivascular invasion (7 8 The red hair/fair skin phenotype characterized by fair skin freckling and inability to tan is associated with the highest melanoma risk of all pigmentation phototypes (9) an YC-1 observation traditionally attributed to reduced UVR protection. However a recent study demonstrated that pheomelanin synthesis contributes to melanomagenesis through a UVR-independent mechanism thought to involve elevated ROS (10)..