Viruses of the family Flaviviridae afflict millions of people worldwide. Hepatitis C virus (HCV), the prototype member of the Hepacivirus genus, chronically infects approximately 2% of the global population. HCV infection can lead to cirrhosis and hepatocellular carcinoma, and is a leading reason for liver transplantation. There is no HCV vaccine, and current therapy, a combination of interferon-alpha and the nucleoside analog ribavirin, is frequently not effective. Viruses of the genus Flavivirus are insect-borne relatives of HCV. Flaviviruses include pathogens such as West Nile, dengue, yellow fever, Japanese encephalitis, and tick-borne encephalitis viruses, many of which are resurging and spreading to new environments. The genus Pestivirus includes animal pathogens such as bovine viral diarrhea virus (BVDV). These viruses cause significant disease in wild and agriculturally important animals. We are interested in understanding how viruses propagate, ways in which they interact with host cells, and how they cause disease. The recent development, by our laboratory and others, of a cell culture infectious system for HCV has drastically increased our ability to study this important pathogen. We are combining genetic analyses in cell culture with biochemical techniques, structural biology, and animal models in attempts to elucidate every aspect of HCV biology and to fight and prevent infectious disease.