With an estimated 170 million infected individuals, hepatitis C virus (HCV) has a major impact on public health. The liver is the primary target organ of HCV, and the hepatocyte is its primary target cell. Attachment of the virus to the cell surface followed by viral entry is the first step in a cascade of interactions between the virus and the target cell that is required for successful entry into the cell and initiation of infection. Using recombinant HCV envelope glycoproteins and HCV pseudotype particles, several cell surface molecules have been identified interacting with HCV during viral binding and entry. These include CD81, highly sulfated heparan sulfate, the low-density lipoprotein receptor, scavenger receptor class B type I and claudin-1. Treatment options for chronic HCV infection are limited and a vaccine to prevent HCV infection is not available. Interfering with HCV entry holds promise for drug design and discovery as the understanding of molecular mechanisms underlying HCV interaction with the host cell is advancing. The complexity of the virus entry process offers several therapeutic targets.