Recent advances in the treatment of hepatitis C virus infection (HCV) have led to high rates of viral cure. However, the use of newly approved protease inhibitors with activity against HCV still requires careful patient selection, counseling, and decision making before initiation of treatment. Laboratory work-up, staging of liver disease, and careful review of comorbid conditions is mandatory. Patients with cirrhosis may require treatment regimens that differ from those without cirrhosis. Because pegylated interferon alfa and ribavirin remain a key part of the treatment regimen, absolute and relative contraindications to their use must be considered. Management of common adverse events including anemia and rash must be embraced by the healthcare provider.