The identity of the cell surface receptor (or receptors) that mediates infection of human hepatocytes by Hepatitis B virus (HBV) has proven elusive. A number of candidates have been proffered over the years, but the lack of good cell culture-based infectivity model systems has tended to frustrate researchers in the field. Most current models of HCV entry recognize a role for four distinct putative cellular co-receptors – the tight junction proteins claudin-1 and occludin, as well as the scavenger receptor-B1 (SR-BI) and the tetraspanin family protein CD81. Delineation of the viral envelope protein sequences involved in virus-cell interactions has lead to the development of a new agent that can reduce spread of HBV in vivo in an animal model. Identification of the cellular partner, or more likely partners, could lead to additional therapeutic interventions to reduce virus spread.