High-throughput genomic methods are now being used to study a wide variety of viral diseases, in an effort to understand how host responses to infection can lead either to efficient elimination of the pathogen or the development of severe disease. This article reviews how gene expression studies are addressing important clinical issues related to hepatitis C virus infection, in which some 15-25% of infected individuals are able to clear the virus without treatment, while the remainder progress to chronic liver disease that can lead to cirrhosis and death. Similar methods are also being used in an effort to identify the mechanisms underlying the failure of some hepatitis C patients to respond to interferon-alpha/ribavirin therapy. By providing a detailed picture of virus-host interactions, high-throughput genomics could potentially lead to the identification of novel cellular targets for the treatment of hepatitis C.