Chronic hepatitis C virus (HCV) infection is a major burden on humanity. The current HCV therapy has limited efficacy, and there is pressing need for new and more effective therapies. Host cell factors that are required for HCV infection, replication and/or pathogenesis represent potential therapeutic targets. Of particular interest are cellular receptors that mediate HCV entry, factors that facilitate HCV replication and assembly, and intracellular pathways involving lipid biosynthesis, oxidative stress and innate immune response. A crucial challenge now is to manipulate such cellular targets pharmacologically for chronic HCV treatment, without being limited by side effects.