HBeAg seroconversion, in association with undetectable levels of hepatitis B virus DNA as determined by polymerase chain reaction, is an important goal in the treatment of patients with HBeAg-positive chronic hepatitis B (CHB). Achievement of sustained HBeAg seroconversion at an early age (<40 years) is associated with a reduced incidence of hepatic complications, increased rates of HBsAg loss and seroconversion and improved survival rates, whether the seroconversion is spontaneous or treatment induced. Patients with HBeAg-positive CHB who achieve sustained HBeAg seroconversion and complete 6–12 months of consolidation therapy are eligible for stopping therapy. In randomized clinical studies involving patients with HBeAg-positive CHB, treatment with pegylated interferon (PegIFN)- α is associated with higher and more durable HBeAg seroconversion rates than are lamivudine and adefovir. More recently, newer generation oral nucleos(t)ide analogs (NAs) have become available. These include entecavir, telbivudine and tenofovir, and they demonstrate superior antiviral potency and efficacy. This review examines the importance of HBeAg seroconversion as an end point for therapy in the treatment of patients with HBeAg-positive CHB, and examines the rates and durability of HBeAg seroconversion with PegIFN and oral NA therapy. The mechanisms for enhanced HBeAg seroconversion rates with new-generation NAs are also discussed.