Chronic hepatitis C virus (HCV) infection remains a global health threat with ∼175 million carriers worldwide. Currently, treatment consists of pegylated interferon alfa plus ribavirin for 12–72 weeks, depending on HCV genotype, baseline viral load, and initial virological response to therapy. Serious adverse effects and limited sustained virological responses with this therapy warrant the need for novel HCV therapies. Specifically targeted antiviral therapies designed to inhibit the HCV serine protease and the RNA-dependent RNA polymerase have recently entered clinical development. Herein, the main characteristics of these new antiviral agents and the most important challenges arising with their use—namely, toxicities and rapid selection of resistance—are discussed.