Epigenetic mechanisms are essential for long-term evolutional and health outcomes and regulation of specific gene expression patterns in mammalian cells. Epigenetic alterations are inherited somatically, and unlike genetic variability, they are reversible and dynamic including histone modifications, DNA methylation, and noncoding RNAs. Recent studies reveal aberrant epigenetic modifications can contribute to improper onset of genetic expressions and play an important role in tumorigenesis. Tumors are heterogeneous cell populations, often consisting of cells with varying degrees of differentiation. Interestingly, the reversible nature of epigenetic changes has led to the emergence of novel anticancer epigenetic targets in multiple cancer therapies. Therefore, determining which of the cell populations has undergone epigenetic alterations, guaranteeing that the therapeutic tools enhance their ability to penetrate into solid tumor masses will increase the success rate of clinical trials in cancer treatment. The use of epi-drugs as monotherapy and a combinatory therapy with other current treatment has demonstrated notable outcomes, including overcoming drug resistance, enhancing of antitumoral effects, and boosting host immune response. This chapter summarizes the concept of epigenetically regulated mechanisms and aberrant epigenetic modifications, especially miRNA-mediated epigenetic changes in the development and progression of cancers and the potential of using this knowledge in planning efficient diagnostic and therapeutic strategies.