Hepatocellular carcinoma (HCC) is the leading cause of death among patients with chronic hepatitis and cirrhosis [1]. Chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) are the most frequent etiological factors for cirrhosis and accounts for approximately 50 and 25 % of all HCC cases, respectively [2]. Other important risk factors for HCC include alcohol consumption and HIV infection. Both are susceptible to exerting a more rapid progression from cirrhosis to HCC due to a synergistic effect in individuals with HBV and/or HCV infections [3]. Accordingly, 80–90 % of patients with HCC have an established background of chronic hepatitis and cirrhosis [4]; consequently, both conditions should be considered components of the HCC-associated multistep process. In this scenario, only surveillance and early diagnosis will potentially reduce the high mortality rate of HCC. Current surveillance of HCC relies on abdominal ultrasonography. This non-invasive, image-based approach has shown nearly 100 % specificity [1]. Unfortunately, ultrasonography requires the expert assessment of images acquired by stateof-the-art equipment, which may not always be available for large-scale surveillance approaches. Alternatively, blood-based biomarkers, such as HCC-secreted proteins to serum or plasma, are an attractive approach because of their non-invasiveness as well as their reproducible and cost-effective assessments. Alpha-Fetoprotein (AFP), a glycoprotein produced by the fetal liver and yolk sac during pregnancy, is the best example of these types of biomarkers. Although levels of [500 ng/mL are indicative of HCC, this is not the case in the early stages of HCC. Moreover, raised concentrations of AFP have been found in patients with HBV and/or HCV infections. Thus, AFP may not be the best candidate for the early diagnosis of HCC. Recently, another HCC-secreted protein, Dickkopf-1 (DKK1), a member of the Dickkopf family involved in embryonic development, has emerged as a potential biomarker for the early diagnosis of HCC. However, DKK1 has been suggested only as a complement to AFP to enhance the accuracy of the serological diagnoses of HCC [5]. Traditionally, the multistep development of HCC proceeding from a naive infection in a normal hepatocyte to chronic hepatitis and cirrhosis and then finally towards fully malignant HCC has been driven by the concept of accumulative damage of the coding genes (i.e. tumorsuppressor genes and oncogenes) [6]. However, over the past decade there has been an exponential growth of knowledge indicating an emerging role of the non-coding regions of the genome, collectively defined as the ‘‘dark matter’’ of genetics [7] or more formally defined as ‘‘epigenetics’’ [8]. This new knowledge is changing current concepts of the multistep process of HCC. Therefore, a modern understanding of the molecular bases of HCC should consider a cooperative effect between both genetic and epigenetic components in the development of HCC [9]. A relevant aspect of non-coding epigenetics is the fact that it represents a shining light for the discovery of novel blood-based biomarkers for human diseases such as HCC. In this issue, Li et al. [10] address this latter aspect of the non-coding epigenetics through the identification of such a biomarker. Li et al. explore one of the four major components of epigenetics, miRNAs. These short 24-bp nucleotides play a major role in the regulation of gene expression at the posttranscriptional level [11]. The A. H. Corvalan (&) Department of Hematology & Oncology, School of Medicine, Pontificia Universidad Catolica de Chile, Marcoleta 391, 8330074 Santiago, Chile e-mail: corvalan@med.puc.cl