By using Infinium HumanMethylation450 BeadChips (Illumina) [24] and integrating the DNA methylome of benign nevi (n = 14) and malignant melanoma from both primary (n = 33) and metastatic (n = 28) sites with gene expression data, we identify, as well as validate in independent patient cohorts, biomarkers for melanoma development (e.g., HOXA9 DNA methylation), tumor progression (e.g., TBC1D16 DNA methylation), and patient prognosis (e.g., PON3 DNA methylation and OVOL1 protein expression). This evidence concerns the gene PON3 and melanoma.