The availability of direct-acting antiviral (DAA) therapy has launched a new era in the management of chronic hepatitis C. Sofosbuvir, a uridine nucleotide analog that inhibits the hepatitis C RNA-dependent RNA polymerase, is the backbone of chronic hepatitis C therapy. Acting at the catalytic site of the polymerase, sofosbuvir is highly potent in suppressing viral replication and has a high genetic barrier to resistance. Sofosbuvir is effective across all hepatitis C genotypes, and is a mainstay of interferon-free combination therapy. In Phase II and III studies, genotype 1 patients who took sofosbuvir in combination with another DAA such as the NS3-4A protease inhibitor, simeprevir, or the NS5A replication complex inhibitors, ledipasvir or daclatasvir, achieved a sustained virologic response rate of over 90%. Harvoni ®, a combination tablet of sofosbuvir and ledipasvir, dosed once daily is recommended for 24 weeks for treatment-experienced genotype 1 patients with cirrhosis, but 12 weeks of therapy is sufficient for all other populations. While genotype 2 (12 weeks or 16 weeks) and treatment-naïve genotype 3 patients (24 weeks) have excellent response rates with sofosbuvir and ribavirin, treatment-experienced cirrhotic genotype 3 patients may need the addition of another DAA such as daclatasvir. Sofosbuvir is efficacious in special populations such as HIV–hepatitis C virus-coinfected patients and liver transplant recipients and has already made a profound impact in these groups. Since it is renally eliminated, patients with advanced kidney disease or on dialysis must await dosing recommendations. Sofosbuvir-based regimens appear to be well tolerated with headache and fatigue being the most common side effects. The opportunity to cure patients with hepatitis C with sofosbuvir combination therapy is likely to change the future for our patients, particularly if the emphasis shifts to identifying those patients unaware that they are infected and providing affordable access to treatment.