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Hepatitis delta virus (HDV) is the smallest known human virus and causes the most severe form of human viral hepatitis, yet it is still not fully understood how the virus replicates and how it interacts with many host proteins during replication. This review aims to provide a systematic review of all the host factors currently known to interact with HDV and their mechanistic involvement in all steps of the HDV replication cycle. Finally, we discuss implications for therapeutic development based on our current knowledge of HDV–host protein interactions.