Hepatocellular carcinoma (HCC) is one of the most frequent human malignancies worldwide with very poor prognosis. It is generally accepted that the progression of HCC is a long-term process with accumulation of multiple genetic and epigenetic alterations, which further lead to the activation of critical oncogenes or inactivation of tumor suppressor genes. HCC is characterized with multiple cancer hallmarks including their ability to proliferate, anti-apoptosis, invade, metastasis, as well as the emerging features such as stem cell properties and energy metabolic switch. The irreversible alterations at genetic level could be detected as early as in the pre-neoplastic stages and accumulate during cancer progression. Thus, they might account for the cancer initiating steps and further malignant transformation. In addition to genetic alterations, epigenetic alterations can affect the cancer transcriptome more extensively. Alterations in DNA methylation, histone modification, miRNAs, RNA editing, and lncRNAs might result in disrupted gene regulation networks and substantially contribute to HCC progression. In this review, the genetic and epigenetic alterations which significantly contribute to the malignant capabilities of HCC will be updated and summarized in detail. Further characterization of those critical molecular events might better elucidate the pathogenesis of HCC and provide novel therapeutic targets for treatment of this deadly disease.