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Hepatitis D virus (HDV) is a defective RNA virus that requires the hepatitis B surface antigen (HBsAg) of the hepatitis B virus (HBV) for its assembly, release, and transmission. HDV is highly pathogenic, causing the least common, but most severe, form of chronic viral hepatitis at all ages. Although significant advances have been made in the treatment of chronic viral hepatitis, targeting HDV remains a major challenge because of the unconventional nature of this virus and the severity of its disease. The virus contains a ribonucleoprotein complex formed by the RNA genome with a single structural protein, delta antigen (HDAg), which exists in 2 forms (small and large HDAg) and is coated by HBsAg. Farnesylation of the large HDAg is essential for anchoring the ribonucleoprotein to HBsAg for the assembly of virion particles. HDV enters into hepatocytes by using the HBV receptor, the sodium taurocholate cotransporting polypeptide (NTCP). Unlike other RNA viruses, HDV does not encode its own polymerase but exploits the host RNA polymerase II for replication. Thus, in contrast to HBV and hepatitis C virus, which possess virus-specific enzymes that can be targeted by specific inhibitors, the lack of a virus-specific polymerase makes HDV a particularly challenging therapeutic target. Treatment of hepatitis D remains unsatisfactory, and interferon-α has been the only approved drug over the past 30 years. This article examines the unconventional nature of HDV, the current management of chronic hepatitis D, and how new insights from the HDV life cycle have led to the development of 3 novel classes of drugs (NTCP receptor inhibitors, farnesyltransferase inhibitors, and nucleic acid polymers) that are currently under clinical evaluation., Competing Interests: This work was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Disease. The authors have no relevant conflicts of interest to disclose.