The role of microRNAs (miRNAs) in human tumorigenesis has been demonstrated by gene profiling and functional studies. In hepatocellular carcinoma (HCC), consistently deregulated miRNAs were identified. Their aberrant expression revealed relations shared with other types of cancer and others unique to HCC, namely the down-regulation of miR-122. Most importantly, functional and molecular studies uncovered mechanisms that linked deregulated miRNAs to cancer-associated pathways, thereby placing their deregulation in a more rational framework. These results improved our knowledge concerning the molecular basis of HCC and helped to increase our understanding about the great clinical potential behind these small molecules. In fact, a number of studies proved that miRNAs may have clinical relevance as bio-pathologic markers for HCC classification, prognostic stratification, early diagnosis or follow-up of patients. Additionally, the demonstration that miRNAs themselves or anti-miRNA oligonucleotides could be successfully used for in vivo modulation of miRNA actions has shown significant potentials in molecularly targeted therapy. In this context, the liver represents an organ of election to test therapeutic possibilities associated with miRNAs.