Current treatments of many advanced malignancies, including melanoma, have failed to significantly reduce mortality rates, necessitating newer approaches. There is now abundant evidence that cancer cells, given the appropriate environmental and molecular context, are capable of remarkable plasticity, including complete reversal of the malignant phenotype. Such reprogramming involves both extrinsic and intrinsic factors and can occur via three routes: perturbations of extracellular matrix-cell receptor interactions, modulation of intracellular signaling pathways, and exploitation of epigenetic inheritance. Studies demonstrate the potential for producing dramatic changes in structural, biochemical, immunological, and functional properties of a broad spectrum of tumor cell types, including melanoma, leading to growth arrest, differentiation, senescence, or self destruction. Translating the promise inherent in tumor cell plasticity to the clinical arena remains a major challenge, but it is likely that a variety of epigenetic methods will play an increasingly important and effective role in the future control of malignant melanoma and other cancers.