// Siqi Fu 1, * , Haijing Wu 1, * , Huiming Zhang 1 , Christine G. Lian 2 and Qianjin Lu 1 1 Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Changsha, Hunan, China 2 Program in Dermatopathology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA * These authors have contributed equally to this work Correspondence to: Lu Qianjin, email: qianlu5860@gmail.com Keywords: melanoma, 5-hmC, 5-mC, epigenetic therapy, TET Received: March 02, 2017 Accepted: May 03, 2017 Published: May 30, 2017 ABSTRACT Melanoma is a malignant tumor of melanocytes and is considered to be the most aggressive cancer among all skin diseases. The pathogenesis of melanoma has not been well documented, which may restrict the research and development of biomarkers and therapies. To date, several genetic and epigenetic factors have been identified as contributing to the development and progression of melanoma. Besides the findings on genetic susceptibilities, the recent progress in epigenetic studies has revealed that loss of the DNA hydroxymethylation mark, 5-hydroxymethylcytosine (5-hmC), along with high levels of DNA methylation at promoter regions of several tumor suppressor genes in melanoma, may serve as biomarkers for melanoma. Moreover, 5-Aza-2′-deoxycytidine, an epigenetic modifier causing DNA demethylation, and ten-eleven translocation family dioxygenase (TET), which catalyzes the generation of 5-hmC, demonstrate therapeutic potential in melanoma treatment. In this review, we will summarize the latest progress in research on DNA methylation/hydroxymethylation in melanoma, and we will discuss and provide insight for epigenetic biomarkers and therapies for melanoma. Particularly, we will discuss the role of DNA hydroxymethylation in melanoma infiltrating immune cells, which may also serve as a potential target for melanoma treatment.