To replicate its genome, a virus needs to cross the plasma membrane of a host cell and get access to cytosolic and/or nuclear components. For an enveloped virus, this involves binding to the plasma membrane, followed by migration of the virion to a microdomain or an endosomal vesicle where fusion between the virion envelope and a host cell membrane occurs. Increasing evidences indicate that virus entry is a tightly regulated process. Although we are still far from understanding the details of hepatitis C virus (HCV) entry, recent data show that this virus enters into target cells in a slow and complex multistep process involving the presence of several entry factors. Initial attachment of the virion may involve glycosaminoglycans and the low-density lipoprotein receptor, and it is followed by the sequential interaction with the scavenger receptor class B type I, the tetraspanin CD81 and tight junction protein Claudin-1, -6 or -9. Furthermore, the identification of EWI-2wint as a new partner of CD81 which blocks E2-CD81 interaction provides additional evidence of the complexity of the HCV entry process. The current knowledge accumulated on HCV entry is summarized in this review.