The percentage of the world’s population chronically infected with the Hepatitis B virus is approximately 5%. This infection is the main cause of chronic liver disease and hepatocellular carcinoma (HCC) globally. From 1990 to 2005 there has been a global decrease in HBV chronic infection prevalence due to expanded vaccination [
1]. However, this condition is still a leading cause of global mortality and its overall burden and relative rank of mortality and disability rose between 1990 and 2013 [
2]. Although there is important geographic variation with 75% of the infected population living in China and the highest prevalence occurring in central sub-Saharan Africa [
1], HBV represents an important global public health issue with a considerable burden to almost all health systems [
3‐
5]. Whilst universal vaccination might provide a key step forward in the HBV global eradication horizon, current therapies only confer clinical control through antiviral activity with few patients achieving HBsAg loss [
6], a functional cure not equivalent to viral eradication. In the era of direct antiviral agents (DAAs), more than 95% of hepatitis C virus (HCV) patients achieve viral eradication, which contrasts with the therapeutic outcome in HBV chronic infection. HBV therapeutic guidelines recommend treatment to prevent liver disease progression, decompensation of cirrhosis and HCC development [
7,
8]. The current standard of care includes administration of nucleos(t)ide analogues (NAs) and peginterferon. Cure of HBV infection is uncommon, influenced by the tenacity of covalently closed circular DNA (cccDNA) in the hepatocytes nuclei. Interferon-based therapies are usually recommended for 48 weeks and may provide more benefit in HBeAg positive patients with low viremia, elevated ALT and HBV genotype-A [
9,
10] however, the benefit in terms of HBV clearance is still low. NAs (Entecavir and Tenofovir), inhibit the HBV polymerase activity and thus viral replication, but with no major impact on cccDNA which is used to transcribe viral RNAs. Consequently, NAs do not prevent the expression of HBV genes from cccDNA or the production of sub-viral particles. Long-term NAs administration achieves HBV eradication in only 5–8% of cases [
6,
11]. Hence, the vast majority of patients require lifelong treatment and rebounding of viral replication frequently follows drug cessation. Furthermore, HCC risk is reduced but not eliminated, even after long-term effective viral suppression [
12]. On the long-term, sustained virological response (SVR) or functional cure occurs in less than 10% of patients [
13,
14]. Hence, new therapies to eliminate HBV are needed. Research developments in HBV molecular virology have resulted in relevant advances in discerning potential therapeutic targets. This review outlines recent pre-clinical and early clinical drug developments aimed at HBV clearance including HBV entry inhibitors, 2
nd generation Core inhibitors, TLR (
toll-like receptor) agonists, anti-sense nucleotides and cccDNA targeting agents.