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Sofosbuvir is a liver-targeting uridine nucleotide prodrug inhibitor of the hepatitis C virus (HCV) RNA-dependent RNA polymerase recently approved by the FDA and EU regulators for treatment of patients infected with genotype 1, 2, 3 and 4 virus. The request for regulatory approval of the fixed-dose combination containing sofosbuvir and the NS5A inhibitor ledipasvir is also under review. Preclinical and clinical studies have shown that sofosbuvir is effective, safe and well tolerated. Review of sofosbuvir's preclinical and clinical profile reveals a drug that has the potential to become the backbone of standard of care. Pursuit of a next generation nucleos(t)ide HCV inhibitor that could compete with sofosbuvir would need to address whatever limitations sofosbuvir exhibits. These include reduced efficacy in genotype 3 patients and use in severe renally impaired patients or those patients currently on drugs that are inducers of P-glycoprotein. However, it has been shown that reduced efficacy in genotype 3 is largely eliminated when sofosbuvir is combined with another oral DAA. Next-generation inhibitors would also benefit by enabling a reduced duration of therapy and an orthogonal resistance profile. The more recent group of nucleos(t)ides in clinical development maintains similarities to sofosbuvir, in that they are uridine nucleotide prodrugs. The question therefore remains whether these new agents will be sufficiently differentiated from sofosbuvir to provide any additional benefit to patients. This paper forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication."