Hepatitis C virus (HCV) infects more than three million new individuals worldwide each year. In a high percent age of patients, acute infections become chronic, eventually progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Given the lack of effective prophylactic or therapeutic vaccines, and the limited sustained virological response rates to current therapies, new approaches are needed to prevent, control, and clear HCV infection.Entry into the host cell, being the first step of the viral cycle, is a potential target for the design of new antiviral compounds. Despite the recent discovery of the tight junction-associated proteins claudin-1 and occludin as HCV co-receptors, which is an important step towards the understanding of HCV entry, the precise mechanisms are still largely unknown. In addition, increasing evidence indicates that tools that are broadly employed to study HCV infection do not accurately reflect the real process in terms of viral particle composition and host cell phenotype. Thus, systems that more closely mimic natural infection are urgently required to elucidate the mechanisms of HCV entry, which will in turn help to design antiviral strategies against this part of the infection process. In a high percent age of patients, acute infections become chronic, eventually progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Given the lack of effective prophylactic or therapeutic vaccines , and the limited sustained virological response rates to current therapies, new approaches are needed to prevent, control, and clear HCV infection. Entry into the host cell, being the first step of the viral cycle, is a potential target for the design of new antiviral compounds. Despite the recent discovery of the tight junction-associated proteins claudin-1 and occludin as HCV co-receptors, which is an important step towards the understanding of HCV entry, the precise mechanisms are still great unknown. indicates that tools that are broadly employed to study HCV infection do not accurately reflect the real process in terms of viral particle composition a Thus, systems that more closely mimic natural infection are urgently required to elucidate the mechanisms of HCV entry, which will in turn help to design antiviral strategies against this part of the infection process.