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Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) are highly prevalent worldwide, causing significant liver disease and thus representing high unmet medical needs. Accordingly, substantial pharmaceutical and clinical research efforts have been made to develop and improve treatments for these viruses. While HBV and HCV are both hepatotropic viruses that can cause similar disease in chronically infected patients, they belong to different viral families. There are substantial differences in the molecular virology of HBV and HCV that have profound implications for therapeutic strategy. In particular, HBV has a long-lived nuclear form of its genome (covalently closed circular DNA) that is able to persist in the face of potent inhibition of viral replication. In contrast, HCV does not have a long-lived genome form and depends on active replication to maintain infection; HCV is therefore much more susceptible to eradication by potent antiviral agents. Additional differences between HBV and HCV with therapeutic implications include the size, structure and heterogeneity of their respective viral genomes. These factors influence the number of targets available for therapeutic intervention, response to therapy among viral genotypes and the emergence of viral resistance. Substantial progress has been made in treating each infection, but unique challenges remain. In this review, key differences in the molecular virology of hepatitis B and C will be presented, highlighting their impact on antiviral therapy (particularly with respect to direct-acting antivirals) and the challenges they present to the cure of each disease.