A wide variety of different viruses use tight junction (TJ) proteins in the course of infection and different mechanisms of pathogen–TJ interactions have been described; pathogens may induce the reorganization or degradation of distinct TJ proteins, reorganization of the cell cytoskeleton, activation of host-cell signaling pathways and/or use TJ proteins as receptors to enter host cells. Most recently, the TJ proteins claudin-1 and occludin have been identified as essential host factors for HCV entry. Furthermore, TJ protein occludin has been shown to play an important role in the species specificity of HCV infection. Recent data suggest that claudin-1 is a promising target for antiviral strategies. The aim of this article is to elucidate the impact of the interplay between pathogens and TJ proteins for pathogen–host interactions, summarize recent findings regarding the role of TJ proteins in HCV entry and highlight the relevance of TJ proteins for the development of novel antiviral strategies.