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Hepatitis C virus (HCV) infections affect about 170 million individuals worldwide and can be life-threatening if left untreated. Over the past three decades, ribavirin and interferon-α have remained the only available medicines for treating hepatitis C sufferers. Given that this combination therapy is partially effective at best and is associated with severe side-effects, there is an unmet need for new molecular entities which inhibit HCV replication. By employing a combination of structure-based drug design together with high-throughput screening approaches, several pharmaceutical companies have been successful in identifying potentially useful compounds for treating HCV infections. This article provides an overview of some of the small-molecule inhibitors that have shown promise so far in clinical trials and which could reach the clinic within the next three years.