Epigenetic dysregulation has recently been recognized as a major cancer hallmark. Novel epigenetic regulators, “epidrugs”, are opening a new window for targeting cancer development or progression, and are considered to be the next therapeutic wave in oncology. Still, clinical applications of epigenetics are very far from routine practice. It is urgent to leverage fundamental knowledge from this rapidly evolving field into concrete clinical applications, such as new opportunities for molecular diagnosis and novel targeted treatments, for patient’s benefit. Understanding the epigenomic alterations combined with genomic features, cell microenvironment and how it can be reprogrammed, integrated with individual clinical data is one the most promising therapeutic strategy for cancer treatment in the personalized medicine and precision immuno-oncology era.