Pegylated interferon-α (PEG-IFN) is still an important treatment option for both HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB) patients even with the availability of potent nucleos(t)ide analogues (NUCs) with a low risk of resistance. The major advantages of PEG-IFN-based treatment include the limited duration of treatment and the good probability of achieving a sustained off-treatment response. Responders to PEG-IFN have an increased probability of HBsAg loss and survival. However, the limited number of patients who achieve a response and the high costs and side-effects associated with PEG-IFN limit its clinical use. The potent NUCs entecavir and tenofovir are therefore often used as a first-line treatment option. Unfortunately, the off-treatment durability of response to NUCs is generally low, requiring long-term continuous therapy. Recent progress making it possible to select patients with a high probability of achieving a response to PEG-IFN, and to adapt therapy early on in probable non-responders, should help further optimize the utilization of PEG-IFN in CHB.