Chronic hepatitis B virus (HBV) infection may progress to liver failure, cirrhosis, and hepatocellular carcinoma (HCC). Current approved antiviral treatments include nucleos(t)ide analogues (NUCs) and immunomodulators, such as pegylated interferon alpha (Peg-IFN). NUCs are safe and generally well-tolerated agents with direct antiviral activities. However, off-treatment durability of response to NUC therapy is low, requiring a long-term or lifelong course of treatment. Peg-IFN treatment has the advantage of a finite duration and a good chance of achieving sustained off-treatment response. However, only a minority of patients has a success response to IFN alone, and high rates of side effects limit its clinical use. Elimination (complete cure) of HBV is hard to achieve with either therapy alone, given that the covalently closed circular DNA (cccDNA) persists stably in the nuclei of infected hepatocytes. Hepatitis B surface antigen (HBsAg) seroclearance is therefore considered the optimal endpoint and a "functional/ clinical cure" for HBV infection, despite the lack of HBV complete clearance. Theoretically, combination of Peg-IFN and NUC with differential mechanisms of actions on HBV is an alternative strategy to treat chronic hepatitis B. Recent studies demonstrated virological or serological benefits of de novo combination therapy with Peg-IFN and NUC, or addition of Peg-IFN (add-on or switch) to an ongoing NUC therapy, but few data exist about the long-term outcomes in patients receiving combination therapy. Currently, several new antiviral or immunomodulatory agents are being explored in experimental models or have reached clinical testing, which may have the potential to complement NUC or IFN-based therapy. This chapter summarizes current combination therapy and novel therapeutic approaches developed to accomplish a cure of chronic HBV infection. © Springer Nature Singapore Pte Ltd. 2018. All rights reserved.