Chronic hepatitis D is a usually severe and progressive liver disease due to infection with the hepatitis delta virus, a unique RNA virus requiring the hepatitis B virus helper function to exert its pathogenic potential. Alpha IFN is at present the treatment of choice for chronic viral hepatitis, but the results obtained in chronic hepatitis D are far from being satisfactory. Available data show that IFN is more likely to be effective if administered to patients with a recent infection (lasting less than 1 year) at high doses (9-10 MU thrice in a week) and for a prolonged length of time (at least 12 months). The optimal timing of IFN treatment remains to be addressed: apart from the clearance of HBsAg and seroconversion to anti-HBs (an event often occurring months to years after completion of a successful IFN treatment) no other early biochemical or virological events can predict a sustained response. Better therapeutic options are therefore needed. Unfortunately, antiviral agents, such as Ribavirin, active against HDV in cell cultures, have failed to confirm their attitude in the clinical setting. In vitro and in vivo evidence points to HBV as a possible target for antiviral therapy in chronic hepatitis D, providing the rationale for trying new deoxynucleotide analogues also in this severe form of hepatitis.