There have been numerous research milestones since the discovery of the hepatitis B virus (HBV) in the 1960s. These mark major advances in the serology and epidemiology of HBV infection, in indentifying the wide clinical spectrum of acute and chronic hepatic diseases as well as the extrahepatic conditions induced by this virus, the molecular biology of the virus including its variants and mutants, its molecular diagnosis and monitoring, the host immune responses to the infecting virus, the pathogenesis and immunopathogenesis of liver disease as well as its natural course and outcome. These landmark discoveries are the firm background for current and future developments in treatment. There are three consecutive and partly overlapping chronological periods to treatment milestones beginning with recombinant standard interferon-alpha (IFN-α) in the 1980s, then oral antivirals from 1998 to the present and in 2005 pegylated IFN-α (PEG-IFN). The renewed interest in PEG-IFN-α treatment is now focused on both HBeAg-positive and HBeAg-negative chronic hepatitis B and it now also aims at HBsAg loss when associated with on-treatment monitoring of serum HBV DNA and HBsAg levels, resulting in the closest thing to a cure of hepatitis B. The impressive progress made in all aspects of hepatitis B research suggests that curative therapy may be developed for all patients and for all phases of HBV infection in the foreseeable future. However for the moment, realistic efforts should be made to make treatment as widely available and affordable as possible and to apply current therapies to significantly reduce HBV morbidity and mortality.