The most distressing change of skin cellular barrier is related to tumorigenesis, as skin cancer has the fourth incidence worldwide. Alongside the genetic alterations in cancer, epigenetic events occur also as early alterations and represent a growing research field, being a potential reservoir of tumor targets in skin cancers and hence means of developing new epi-drugs. DNA methylation, histones alteration, and miRNA levels are briefly the main tools for executing the epigenomic program in cancer cells. Exploiting in depth all these deregulations has shown that epigenome is a druggable collection of tumor targets and alternative therapies. These novel insights within epigenome could be viewed in several angles: as new drugs, repurposed ones or could be combined with innovative immunotherapy and targeted therapies. As such, epigenome machinery is actively enrolled in the medicine-personalized era and endows very promising strategies for anti-cancer combat.