Development of more effective hepatitis C (HCV) antivirals has been rapid. The addition of orally administered medications that target the virus (direct acting antivirals [DAA]) to pegylated interferon and ribavirin have dramatically increased sustained virologic response rates in genotype 1-infected patients. However, the side effect profile remains challenging and the dosing schedule complicated. The DAAs currently in development possess the promise of once- or twice-daily dosing schedules, improved tolerance profiles, higher resistance barriers, and pan-genotypic antiviral activity. Emerging interferon-sparing, combination DAA data demonstrates that an interferon is not essential to achieve sustained virological response. This will expand the proportion of HCV-infected patients who can be considered for therapy and will allow for better-tolerated regimens. Expertise in HCV antiviral resistance, drug metabolism, and drug-drug interactions and optimization of drug adherence are now key requirements in the DAA era.