The hepatitis C virus (HCV) is a major medical problem with at least 130 million infected individuals worldwide. Over the last decade multiple host factors required for HCV cell entry have been identified, but a detailed understanding of their mechanistic interplay remains elusive. Nonetheless, recent advances in defining species-specific barriers of HCV transmission have allowed the identification of a minimal set of entry factors that are required for HCV infection of rodent cells and has culminated in an animal model that recapitulates HCV entry in vivo. A detailed understanding of the viral uptake pathway is imperative to define new drug targets allowing for more effective intervention against this devastating disease.