Hepatitis C virus (HCV) is believed to have infected over 170 million individuals worldwide and is considered a global health problem. Infection with HCV is known to lead to chronic liver disease, cirrhosis and eventually hepatocellular carcinoma. The search for direct-acting antiviral agents that inhibit the replication of HCV has focused on the HCV non-structural proteins of which the NS5B RNA-dependent RNA polymerase is one. Nucleoside inhibitor strategies have proven fruitful in the identification of potent and selective inhibitors of HCV polymerase. The 2â ²-F-2â ²-C-methyl class of nucleos(t)ides have proved particularly useful in that this class of nucleos(t)ides show good potency, selectivity, broad genotype coverage and demonstrate a high barrier to resistance. RG7128 and PSI-7851 are members of the 2â ²-F-2â ²-C-methyl class of nucleos(t)ides. RG7128 is an ester prodrug of PSI-6130, a cytidine nucleoside, and has demonstrated potent clinical efficacy in genotype 1,2,3 and 4 patients. RG7128 is currently in Phase IIb clinical study. PSI-7851, a liver targeting prodrug, has demonstrated clinical efficacy and an acceptable safety profile in genotype 1 patients. The discovery and clinical development of RG7128 and PSI-7851 are presented.