Hepatocellular carcinoma (HCC) is the most common type of liver malignancy and one with high fatality. Its 5-year survival rate remains low and thus, there is a need for improvement of current treatment strategies as well as development of novel targeted methodologies in order to optimize existing therapeutic protocols. To this end, only recently, it was discovered that its pathophysiology also involves epigenetic alterations in DNA methylation, histone modifications and/or non-coding microRNA patterns. Unlike genetic events, epigenetic alterations are reversible and thus potentially considered to be an alternative option in cancer treatment protocols. In this review, we describe the general characteristics and resulted major alterations of the epigenetic machinery as well as current state of progress of epigenetic therapy (via different single or combinatorial experimental approaches) in HCC.