The hepatitis delta virus (HDV) genome has only one open reading frame, which encodes the viral small delta antigen. After RNA editing, the same open reading frame is extended 19 amino acids at the carboxyl terminus and encodes the large delta antigen. These two viral proteins escort the HDV genome through different cellular compartments for the complicated phases of replication, transcription and, eventually, the formation of progeny virions. To orchestrate these events, the delta antigens have to take distinct cues to traffic to the right compartments and make correct molecular contacts. In eukaryotes, post-translational modification (PTM) is a major mechanism of dictating the multiple functions of a single protein. Multiple PTMs, including phosphorylation, isoprenylation, acetylation, and methylation, have been identified on hepatitis delta antigens. In this chapter we review these PTMs and discuss their functions in regulating and coordinating the life cycle of HDV.