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Melanoma is the most severe skin cancer characterized by a bad prognosis at metastatic stages due to resistance to most classical chemotherapies. Invasion of melanoma cells into the surrounding microenvironment locally and at distance of the primary tumour, is facilitated by expression of proteases that degrade the extracellular matrix. Matrix metalloproteinases (MMP) have been long thought as potential therapeutic targets as they are involved in several steps of tumour progression. However, based on this general concept, broad spectrum MMP inhibitors showed weak anticancer potential. Furthermore, MMPs are also expressed by stroma and infiltrating cells. Although, inflammatory conditions lead to uncontrolled expression of MMPs leading to massive matrix destruction, these enzymes are also essential for immune cells to migrate towards the tumour site, and hence mount an anti-tumoral response. During stromal reaction, MMPs also act as non-matrix deteriorating enzymes, and thus modulating the inflammatory response through limited proteolysis of cytokines and chemokines. MMPs contribution to these processes depends on their activity and their expression. Besides the classic control level of transcription by a variety of growth factors and cytokines, the contribution of epigenetic mechanisms on MMPs expression was demonstrated of great importance to extend our knowledge about the role of these enzymes in a specific context such as melanoma progression. Understanding MMPs regulation by epigenetic drugs in melanoma and infiltrated cells will provide a new platform to develop efficient therapies. The therapeutic implication of epigenetic mechanisms to switch a pro-tumoral inflammatory towards an immune anti-tumoral response will be an exciting challenge in which MMPs expression could play a major role.