Hepatitis D virus (HDV) is a small satellite virus of hepatitis B virus (HBV) requiring HBV infection to complete its life cycle. It has been recently estimated that 13% of chronic HBV infected patients (60 million) are co-infected with HDV. Chronic hepatitis D is the most severe form of viral hepatitis with the highest risk to develop cirrhosis and liver cancer. Current treatment is based on pegylated-interferon-alpha which rarely controls HDV infection and is complicated by serious side effects. The development of novel antiviral strategies based on host targeting agents has shown promising results in phase I/II clinical trials. This review summarizes HDV molecular virology and physiopathology as well as new therapeutic approaches targeting HDV host factors.