HBeAg negative chronic hepatitis B (CHB) is a frequent, progressive and difficult-to-cure phase of CHB. The end-point of therapy is to persistently suppress viral replication to halt progression of liver disease. Two different treatment strategies are currently available: a short-term course of pegylated interferon alpha (PEG-IFN) or long-term therapy with nucleot(s)ide analogues (NA), i.e. entecavir or tenofovir. Young patients with mild-to-moderate stages of liver disease can benefit from a 48-week course of PEG-IFN, while NA may be preferred in patients with more severe liver disease, in older patients, and in those who do not respond, are unwilling or have contraindications to PEG-IFN. Nucleot(s)ide analogues provide persistent viral suppression and biochemical normalization in almost all patients, together with the regression of fibrosis and the prevention of decompensation, but the effect on hepatocellular carcinoma rates is limited. Thus, NAs have become the most popular treatment strategy worldwide but lifelong administration is associated with high cost, unknown safety and adherence issues and an unknown risk of drug-resistance over time as well as limited rates of HBsAg seroclearance. On the other hand, PEG-IFN treatment may achieve a SVR in nearly a quarter of patients ultimately leading to HBsAg loss in almost 30–50%. Interestingly, response rates to PEG-IFN may further increase with more careful patient selection based on age, ALT and HBV DNA levels at baseline and by applying early on-treatment stopping rules based on HBV DNA and HBsAg kinetics. The combination of NA and PEG-IFN is not currently recommended but numerous studies are ongoing.