MicroRNAs are small endogenously expressed RNA molecules which are involved in the process of silencing gene expression through translational regulation.The polycistronic miR-17-92 cluster is the first microRNA cluster shown to play a role in tumorigenesis.It has two other paralogs in the human genome,the miR-106b-25 cluster and the miR-106a-363 cluster.Collectively,the microRNAs encoded by these clusters can be further grouped based on the seed sequences into four families,namely the miR-17,the miR-92,the miR-18and the miR-19 families.Over-expression of the miR-106b-25 and miR-17-92 clusters has been reported not only during the development of cirrhosis but also subsequently during the development of hepatocellular carcinoma.Members of these clusters have also been shown to affect the replication of hepatitis B and hepatitis C viruses.Various targets of these microRNAs have been identified,and these targets are involved in tumor growth,cell survival and metastasis.In this review,we first describe the regulation of these clusters by c-Myc and E2F1,and how the members of these clusters inturn regulate E2F1 expression forming an auto-regulatory loop.In addition,the roles of the various members of the clusters in affecting relevant target gene expression in the pathogenesis of hepatocellular carcinoma will also be discussed. MicroRNAs are small endogenously expressed RNA molecules which are involved in the process of silencing gene expression through translational regulation. The polycistronic miR-17-92 cluster is the first microRNA cluster shown to play a role in tumorigenesis. It has two other paralogs in the human The miR-106b-25 cluster and the miR-106a-363 ​​cluster. Collectively, the microRNAs encoded by these clusters can be further grouped based on the seed sequences into four families, namely the miR- 17, the miR- 92, the miR-18 and the miR-19 families. Over-expression of the miR-106b-25 and miR-17-92 clusters has been reported not only during the development of cirrhosis but also subsequently during the development of hepatocellular carcinoma. Members of these clusters have also been shown to affect the replication of hepatitis B and hepatitis C viruses. Difficult targets of these microRNAs have been identified, and these targets are involved in tumor growth, cell survival and metastasis. in this review, we fi rst describe the regulation of these clusters by c-Myc and E2F1, and how the members of these clusters inturn regulate E2F1 expression forming an auto-regulatory loop. In addition, the roles of the various members of the clusters in affecting relevant target gene expression in the pathogenesis of hepatocellular carcinoma will also be discussed.