The development of a protective HCV vaccine has been among the most diffcult challenges since the discovery of the virus for a number of reasons. First, despite the consistent efforts of many laboratories, there is still no permissive system that consistently replicates HCV at high enough levels to evaluate antibodies that may be neutralizing (Table 11.1 and Ch. 11). Second, with the exception of the chimpanzee, which is expensive, endangered, and diffcult to work with, there are no convenient animal models that are susceptible to HCV and that could be used for candidate vaccine challenge studies (Section 1.2). Third, the genotype, subtype and quasispecies nature of HCV (Weiner et al., 1992; Bukh et al., 1997; Simmonds et al., 1993, 1997) (Section 3.2) may require the construction of polyvalent vaccines that would protect against a large number of closely related epitopes. The fact that the genetic heterogeneity of the virus can change rapidly in an infected individual (Ogata et al., 1991), and that antiviral immunity may select for neutralization escape mutants (within HVR1) (Martell et al., 1992; Weiner et al., 1992; Shimizu et al., 1994) as well as CTL escape mutants (Weiner et al., 1995), may limit the effectiveness and utility of any vaccine. Fourth, it is not clear whether the envelope polypeptides contain all of the antigenic determinants required for effective neutralization (Chien et al., 1993).