Infection by the hepatitis B (HBV) and C (HCV) viruses is a major cause of morbidity and mortality world-wide. The clinical outcomes of infection by these viruses (e.g., chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma) depend on several factors related to the host and the viral agent. Among the latter, factors associated with the response to current antiviral therapies, such as the emergence of resistance mutants and the genotype responsible for the infection, are gaining increasing importance. As has been established for human immunodeficiency virus (HIV), the presence of resistance mutations in the viral polymerase constitutes the main problem for treating HBV infection with approved drugs and those recently applied. Methods have been developed to detect these mutations, as well as algorithms to predict the response to treatment. The outcome of treatment for HCV infection is highly influenced by the viral genotype, however, and our understanding of the molecular basis for the response to interferon in these patients has grown considerably in recent years.