Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease worldwide and represents a major public health problem. Viral attachment and entry – the first encounter of the virus with the host cell – are major targets of neutralising immune responses. Thus, a detailed understanding of the HCV entry process offers interesting opportunities for the development of novel therapeutic strategies. Different cellular or soluble host factors mediate HCV entry, and considerable progress has been made in recent years to decipher how they induce HCV attachment, internalisation and membrane fusion. Among these factors, the scavenger receptor class B type I (SR-BI/SCARB1) is essential for HCV replication in vitro, through its interaction with the HCV E1E2 surface glycoproteins and, more particularly, the HVR1 segment located in the E2 protein. SR-BI is an interesting receptor because HCV, whose replication cycle intersects with lipoprotein metabolism, seems to exploit some aspects of its physiological functions, such as cholesterol transfer from high-density lipoprotein (HDL), during cell entry. SR-BI is also involved in neutralisation attenuation and therefore could be an important target for therapeutic intervention. Recent results suggest that it should be possible to identify inhibitors of the interaction of HCV with SR-BI that do not impair its important physiological properties, as discussed in this review.