The family of the Flaviviridae contains 3 genera: (i) the hepaciviruses, to which belongs Hepatitis C virus (HCV), (ii) the flaviviruses and (iii) the pestiviruses. Over 140 million people, more than four times the number of HIV-positive individuals, are chronically infected with the HCV. Hepatitis G virus (HGV) has not yet been assigned to a genus. The impact of this recently discovered virus is yet to be established. Infections with flaviviruses such as Yellow Fever virus (YFV), Dengue Fever virus (DENV), Japanese Encephalitis virus (JEV) and Tick-borne Encephalitis virus (TBEV) are emerging world-wide. The Pestiviruses, Bovine Viral Diarrhea virus (BVDV), Classical Swine Fever virus (CSFV) and Border Disease virus (BDV) have a serious impact on life-stock. At present, only treatment with interferon, alone or combined with ribavirin, has been approved for the treatment of HCV infections. No specific antivirals are available for the treatment of infections with Hepaci-, Flavi- or Pestiviruses. Possible targets for inhibition of the replication of Flaviviridae are the binding to, and the uptake of the virus in the cell; the internal ribosomal entry site (IRES) of Hepaci- and Pestiviruses; viral proteases; the viral RNA-dependent RNA polymerase and the viral helicase. The search for specific inhibitors of HCV replication is hindered by the absence of an efficient cell culture system for propagation of this virus. In addition, small laboratory animals, including mice, are not susceptible to HCV infection. Flaviviruses may cause infection in mice, but do so mainly following direct intracerebral inoculation. We have established a small animal model for flavivirus infections in SCID mice inoculated peripherally with the murine flavivirus Modoc.