MicroRNAs (miRNAs), which are inhibitors of gene expression, participate in diverse biological functions and in carcinogenesis. In this study, we show that liver‐specific microRNA‐122 (miR‐122) is significantly down‐regulated in liver cancers with intrahepatic metastastasis and negatively regulates tumorigenesis. Restoration of miR‐122 in metastatic Mahlavu and SK‐HEP‐1 cells significantly reduced in vitro migration, invasion, and anchorage‐independent growth as well as in vivo tumorigenesis, angiogenesis, and intrahepatic metastasis in an orthotopic liver cancer model. Because an inverse expression pattern is often present between an miRNA and its target genes, we used a computational approach and identified multiple miR‐122 candidate target genes from two independent expression microarray datasets. Thirty‐two target genes were empirically verified, and this group of genes was enriched with genes regulating cell movement, cell morphology, cell‐cell signaling, and transcription. We further showed that one of the miR‐122 targets, ADAM17 (a disintegrin and metalloprotease 17) is involved in metastasis. Silencing of ADAM17 resulted in a dramatic reduction of in vitro migration, invasion, in vivo tumorigenesis, angiogenesis, and local invasion in the livers of nude mice, which is similar to that which occurs with the restoration of miR‐122. Conclusion: Our study suggests that miR‐122, a tumor suppressor microRNA affecting hepatocellular carcinoma intrahepatic metastasis by angiogenesis suppression, exerts some of its action via regulation of ADAM17. Restoration of miR‐122 has a far‐reaching effect on the cell. Using the concomitant down‐regulation of its targets, including ADAM17, a rational therapeutic strategy based on miR‐122 may prove to be beneficial for patients with hepatocellular carcinoma. (HEPATOLOGY 2009.)