The HCV RNA-dependent RNA polymerase is an essential enzyme in HCV viral replication and has been a prominent target in the search for therapies to treat individuals infected with HCV. The development of both nucleoside and nucleotide HCV inhibitors has been pursued because of their potential for showing pangenotypic activity and because of their high barrier to resistance. Even though nucleoside inhibitors were shown to be effective in a clinical setting, their potency limited their effectiveness. The exploitation of prodrug strategies to deliver nucleoside 5'-monophosphates has resulted in the development of a number of very potent inhibitors of HCV replication. In addition, several of these nucleotide prodrugs have demonstrated liver-targeting characteristics when administered orally. Human clinical studies have shown that a number of nucleotide prodrugs are potent inhibitors of viral replication leading to significant reductions in viral load when given orally. Combinations of these nucleotide prodrugs with either pegylated interferon-α and ribavirin or another direct acting antiviral alone has lead to cure rates as high as 100% after only 12 weeks of therapy. The combination of a nucleotide prodrug and another direct-acting antiviral agent holds the promise of delivering an interferon-free therapy for HCV patients thus eliminating the undesirable side effects associated with taking interferon.