The observation that a poor IFN response in clinical trials correlated with a high degree of variability of quasispecies (Kanazawa et al., 1994; Chayama et al., 1995; Koizumi et al., 1995) (Ch. 9) implies that mutations in one or more HCV gene products may alter the sensitivity of the virus to IFN. Further work revealed the presence of an IFN sensitivity-determining region (ISDR) within the carboxy-terminal region of the NS5A polypeptide that spans amino acid residues 2209–2248 (Enomoto et al., 1995, 1996), which may be selected for during the course of IFN therapy (Enomoto et al., 1994). Patients that failed to respond to IFN therapy had one sequence within this region, while patients that were IFN responders had a ISDR sequence that differed in 4–11 amino acid residues. Among HCV sequences reported in the literature, the NS5A sequence associated with IFN resistance was identical to that of subtype 1b (Kato et al., 1990), implying that subtype 1b was associated with IFN resistance. The existence of an ISDR was confirmed by independent studies in Japan (Chayama et al., 1997; Kurosaki et al., 1997), but the correlation broke down when similarly designed studies were reported from other countries (Hofgartner et al., 1997; Squadrito et al., 1997).