Hepatitis C virus is a significant public health problem. Current drug regimens have low efficacy against some hepatitis C virus genotypes, while no vaccine is available. The absence of an efficient cell culture system and an accessible small animal model to study hepatitis C virus replication and pathogenesis are major obstacles to the development of effective antiviral therapies. Studies of surrogate model systems, either related viruses or chimeric viruses containing part of the hepatitis C virus genome, have given insight into hepatitis C virus replication, in addition to being a powerful tool for drug discovery. The recent development of an efficient system for the initiation of replication in cell culture provides a viable screen for inhibitors of hepatitis C virus replication. It also brings us much closer to the ultimate goal of an infectious cell culture system for hepatitis C virus.