Chronic hepatitis B virus (HBV) infection continues to be a major health burden worldwide. Currently available antiviral treatment options for chronic hepatitis B include pegylated interferon alpha (PEG-IFN) or nucleos(t)ide analogues (NAs). The major advantages of NAs are good tolerance and potent antiviral activity associated with high rates of on-treatment response to therapy. The advantages of PEG-IFN include a finite course of treatment, the absence of drug resistance, and an opportunity to obtain a durable post-treatment response to therapy. The use of these two antiviral agents with different mechanisms of action in combination is theoretically an attractive approach for treatment. Although several studies have confirmed certain virological advantages of combination therapies, pivotal prospective studies demonstrating long-term clinical benefit to patients are still missing and monotherapy with PEG_IFN or NAs remains the therapy of choice. Furthermore, with the current treatment approaches, only a limited number of patients reach the aim HBsAg loss, which is closest to clinical cure. The limited efficacy of current approved therapeutic regimens demands the development of more efficient therapeutic approaches enabling not only suppression of viral replication, but resolution of HBV infection. The unique replication strategy employed by HBV enables its persistence within the infected hepatocytes. As a consequence, relapse of viral activity is commonly observed after cessation of treatment. Both the persistence of the HBV genome, which forms a stable minichromosome, the covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes, as well as the inability of the immune system to resolve chronic HBV infection are believed to be key mechanisms of HBV chronicity. The recent development and availability of innovative in vitro and in vivo systems and sensitive molecular techniques have opened new possibilities to study the complex network of interactions that HBV establishes with the host in the course of infection and to define new targets for antiviral strategies. Several new antiviral or immunomodulatory compounds have reached preclinical or clinical testing with the aim of a clinical cure of chronic HBV with the loss of HBsAg. This review summarizes the most recent therapeutic strategies designed to directly target the virus or to improve immune responses during chronic HBV infection.