The lack of tissue culture systems that consistently support HCV replication (Ch. 11) has prompted the development of other assays with individual virus gene products that may be converted into high throughput screens for drug screening and discovery. A powerful tool in the design of such assays has been the development of cell lines and cell-free systems that express one or more HCV proteins (Table 11.1). For example, the recent development of HCV subgenomic replicons in Huh7 cells provides opportunities to test antiviral compounds against the virus polymerase, which is responsible for the replication of the subgenomic plasmids in this system (Lohmann et al., 1999; Blight et al., 2000). In addition, the development of cell lines or chimeric viruses with replication dependent upon HCV NS3 expression (Hirowatari, Hijikata & Shimotohno, 1995; Hahm et al., 1996; Song et al., 1996; Filocamo, Pacini & Migliaccio, 1997) will allow screening against the NS3 protease and helicase. Another important contribution has been the publication of the crystal structure for several HCV proteins. This information will be central to the rational design of inhibitors based upon the three-dimensional active sites of the corresponding virus proteins. For example, the recent crystallographic structure of the NS3 helicase domain (Yao & Weber, 1998; Kwong, Kim & Lin, 2000) (Sections 2.4 and 2.5), which recognizes and unwinds double-stranded RNA in an NTP-dependent reaction during virus replication, has revealed amino acid residues that could be sites for inhibitor design and interaction.