Chronic hepatitis C virus (HCV) infection is the leading cause of chronic liver disease. Current therapy using pegylated interferon-α with ribavirin is poorly tolerated and confers an overall sustained virological response around 56%. Compounds exhibiting an improved safety profile with similar or enhanced antiviral properties may represent future treatment options. Several drug discovery programmes are ongoing to directly target the viral enzymes involved in HCV replication. Recent clinical success using a peptidomimetic inhibitor of the viral serine protease has demonstrated proof-of-concept for the use of direct antiviral agents in reducing viral load. The RNA-dependent RNA polymerase (RdRp) of HCV is also required for viral RNA replication and thus represents an attractive drug discovery target. Preclinical characterization of several non-nucleoside inhibitors (NNIs) of the HCV RdRp have been described, including a promising series of benzothiadiazine derivatives which have been shown to efficiently block viral RNA synthesis in HCV replicon cell systems. Herein, the antiviral activity, mode of action, resistance profiling and therapeutic potential of the benzothiadiazine class of compounds for clinical development are explored.