Hepatocellular carcinoma (HCC) is the liver's most common primary malignancy, with over half a million new cases diagnosed each year and being the fourth leading cause of cancer death, worldwide. The poor prognosis of HCC is largely related to late diagnosis. Historically, serum alpha-fetoprotein and diagnostic imaging have been primary diagnostic modalities. However, the poor prognosis due to late diagnosis of HCC has proven unacceptable and, recently, significant efforts have been devoted to identifying patients with early stage HCC. Molecular biomarkers can provide additional and relevant information about the biological behavior of these tumors. Research in biomarker combinations may provide more accurate and valuable information for the future individualized HCC diagnosis and/or prognosis. Several biomarkers with prognostic significance have been identified, however all of them have been studied retrospectively. Furthermore, of all different molecular signatures that have been published, very few have been externally validated. The aim of this review is to analyze the most relevant emerging biomarkers of HCC.