There are 160–170 million people with chronic hepatitis C virus (HCV) infection worldwide. The marketing of protease inhibitors (PIs) has been a milestone in the history of HCV therapy. In phase III studies, up to 75% of the patients achieved a sustained virological response (SVR) after triple therapy with pegylated-interferon (PEG-IFN)-α, ribavirin (RBV) and boceprevir (BOC). However, triple regimens are more expensive and associated with drug–drug interactions (DDIs) and more adverse events (AEs). According to results in ‘real-world’ settings, safety seems to be limited, in particular in patients with advanced liver disease. To optimize efficacy while minimizing AEs as well as costs, the optimal treatment strategy must be determined for BOC. Optimizing treatment is based on patient selection, the most efficient treatment design, management of side effects and the challenge of DDIs. Therapy-associated risks, treatment urgency and chances of SVR must all be considered for patient selection. In addition, certain differences between the two approved PIs may help identify the ideal candidates for each HCV PI. Optimal treatment design is based on the results of phase II and III studies, in which different approaches have been tested including ‘lead-in’ and response-guided strategies. Treatment regimens and stopping rules recommended by the FDA and EMA should normally be followed. Still, there are some cases in which more personalized strategies may be more promising. Management of side effects is a major challenge and plays a crucial role in ensuring safety and adherence.