Products that are currently used in the treatment of chronic hepatitis B include interferon-alpha (IFNa: standard or pegylated) (PEG-IFNa) and nucleos(t)ide analogues (NAs). NAs are used in most HBeAg-negative chronic hepatitis B patients for several reasons. They can be prescribed to all chronic HBV patients, even those with contraindications to IFNa; and even IFNa candidates are usually treated with NAs because of their advantages. Administration of NAs is easier (one oral tablet per day compared with subcutaneous IFNa injections), tolerance is excellent and the safety profile is good, whereas IFNa may have adverse events and often worsens the patients’ quality of life. The current first-line NA options, entecavir (ETV) and tenofovir (TDV), have minimal or no risk of long-term resistance and a virological response is achieved in almost 100% of adherent HBeAg-negative patients, thus modifying the long-term outcome. The need for long-term, perhaps indefinite, treatment is the main limitation of NAs and the finite duration (48 weeks), the main advantage of IFNa, especially in young patients of reproductive age. However, at most 25% of IFNa-treated HBeAg-negative patients achieve a sustained off-treatment response and therefore >75% of them will eventually receive NAs, even if they start with IFNa. As there will always be concerns about safety and family planning issues with long-term NA therapy, NAs should be used carefully, particularly in young chronic hepatitis B patients with mild liver disease. Novel therapeutic options are needed to increase the rates of HBsAg loss and sustained off-treatment responses.