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Treatment of Hepatitis C Virus (HCV) infection is rapidly evolving with the introduction of direct acting antiviral agents (DAA). HCV NS5A replication complex inhibitors, exemplified by Daclatasvir (BMS-790052), represent a new class of DAA. The exceptional in vitro potency (EC50 values at pM to low nM range) and broad genotype coverage of NS5A inhibitors have translated to robust anti-HCV effects in infected patients, making NS5A inhibitors an essential component of effective HCV DAA combination therapies. On the basis of drug-induced resistance substitutions and computer modeling, NS5A inhibitors most likely act at the N-terminus of NS5A (domain I). Mechanism of inhibition studies to elucidate the exquisite potency of these inhibitors have generated several working models.