Estimates suggest that there are currently 200 million people, worldwide, infected with the Hepatitis C virus and these numbers are anticipated to rise within the next decade. Despite intensive research over the past twenty years, there are still no vaccines available to prevent infections and existing antiviral treatments are associated with serious complications. As a result, there is a pressing need for more effective and broadly applicable therapeutics. As potential treatments, drugs targeting particular steps in the replication of the virus are being developed. Hepatitis C virus polymerase, NS5B, is essential for the replication of the virus and as a result has been targeted for the development of new antiviral agents. Crystallographic studies of the enzyme bound to its ligands, including RNA templates, nucleotides or inhibitors, should provide more information on the mechanism of the enzyme, which can ultimately be exploited for drug-design studies.