Chronic hepatitis C virus (HCV) infection is the major etiology and the reason of chronic liver disease, liver cirrhosis, hepatic decompensation, hepatocellular cancer and liver transplantation. Less than half of patients with HCV-related chronic hepatitis achieve sustained viral clearance with current pegylated interferon and ribavirin (P+R) combination therapy. Due to the insufficient treatment success, an extended search for new, direct acting anti-HCV agents (DAAs) is ongoing, already leading to submissions of applications for marketing authorization of the protease-inhibitors boceprevir and telaprevir. Both are effective only in triple combinations with P+R. Studies demonstrate a 50% success rate advantage for triple therapies above current standards. In addition, treatment duration can be shortened, and half of the patients who failed previous therapy with P+R can be cured with triple therapies. A major concern with new DAAs is rapid development of DAA-resistant viral mutants, a reason as well as a consequence of insufficient triple therapy. Clinical studies with boceprevir and telaprevir are reviewed in this paper.