Hepatitis Delta is the most severe form of viral hepatitis in humans. The hepatitis Delta virus (HDV) is a defective RNA virus, which requires the hepatitis B virus (HBV) surface antigen (HBsAg) for complete replication and transmission. Several studies have shown that chronic HDV infection leads to more severe liver diseases than chronic HBV mono-infection, with an accelerated course of fibrosis progression, possibility of a slightly increased risk of hepatocellular carcinoma development and early decompensation in the setting of established cirrhosis. Only interferon-alfa treatment has been shown to exert some antiviral activity against HDV and has been linked to improve the clinical long-term outcome. Data on the use of PEGylated interferon (PEG-IFN) confirm earlier findings, leading to prolonged virological off-treatment responses in about one quarter of patients, but long-term HDV RNA relapses may occur. HBsAg clearance should be the preferred endpoint of interferon-based therapies of HDV. Alternative treatment options including HBV entry inhibitors and prenylation inhibitors are currently in early clinical development.