Chronic hepatitis delta (CHD) affects approximately 10-20 million people worldwide and represents the most severe form of chronic viral hepatitis, as it is characterized by high rates of progression to cirrhosis and its complications (end-stage liver disease, hepatocellular carcinoma). In the last 30 years, the only treatment option for CHD has been represented by the off-label administration of Interferon (or Pegylated Interferon)-alpha: antiviral treatment, however, resulted in suboptimal (20-30%) virological response and was burdened by several side effects, de facto contraindicating Interferon (IFN) administration in patients with more advanced liver disease. Recently, Bulevirtide (BLV), a first-in-class HBV-HDV entry inhibitor blocking Na -taurocholate co-transporting polypeptide (NTCP), has provided very promising efficacy data in Phase II and Phase III (interim analysis) trials as well as in preliminary real-life reports. In July 2020, BLV has granted conditional approval by EMA for treatment of compensated CHD, at the dose of 2 mg/day by self-administered subcutaneous injections. In Phase II and Phase III trials, BLV was evaluated at different doses (2 vs. 10 mg/day) for 24 or 48 weeks, either in monotherapy or in combination with PegIFN. Administration of BLV monotherapy for 24 or 48 weeks resulted in 50%-83% virological response (HDV RNA ≥ 2 Log decline) rates and 45%-78% ALT normalization. Combination therapy with PegIFN provided synergistic effects. These results were replicated in real-life studies and confirmed also in patients with advanced cirrhosis and clinically significant portal hypertension. BLV treatment was optimally tolerated, resulting only in an asymptomatic increase of bile acids.