MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of a large fraction of genes in animals, plants, and protozoa. miRNA-mediated gene repression occurs posttranscriptionally, generally by base-pairing to the 3'-untranslated regions of target mRNAs, which inhibits protein synthesis and destabilizes the mRNA. In this chapter, we discuss the biological functions of miR-122, a highly abundant, liver-specific miRNA. We will review how studies of miR-122 helped to establish important new paradigms of miRNA-mediated regulation, as well as identifying miR-122 as a factor implicated in important human diseases, including cancer and hepatitis C. We discuss antisense strategies targeting miR-122 as a potential therapeutic approach to treat hepatitis C and possibly other diseases.