Hepatitis B is an infectious inflammatory disease of the liver, which is caused by hepatitis B virus (HBV). Nowadays, the dramatic development of new HBV inhibitors is focused on discovering diverse non-nucleosides compounds with either novel structures or new mechanisms of action. In this review, we focus on the recent advances in discovery, structural modifications and biological activities studies of several distinct classes of synthetic non-nucleosides small molecular compounds with new mechanisms.Currently, clinically available drugs against HBV infection approved by FDA comprise interferon (Interferon α and Pegylated Interferon α-2a) and nucleos(t)ide analogues (Lamivudine, Clevudine, Adefovir, Entecavir, Telbivudine, and Tenofovir, Fig.1) 5, 6. Interferon can develop immune ability of the patients. But it is not ideal for its adverse side effects and low cure rate. Nucleos(t)ide analogues are kind of reverse transcriptase inhibitors (NRTIs), which target at the HBV polymerase and effectively restrain the most important progress of the virus particle's life cycle-HBV DNA replication. Regrettably, NRTIs are far from perfect because of the mutation domain of the reverse transcriptase. The emergence of drugresistant virus strains and the appearance of severe side effects 7- 9 encourage the development of novel non-nucleoside analogues targeting non-polymerase viral or host proteins. After years of efforts, much progress have been achieved in the discovery of natural products and synthesized compounds as potent anti-HBV agents 10, 11. The natural product-derived compounds can be used with the existing anti-HBV agents to reduce the possibility of drug resistance and show a synergetic effect. In contrast, the small synthetic heterocyclic molecules, with the characteristics of easy synthesis and drug-likeness, have distinguishing advantages over natural compounds. Recent work about the application of heterocyclic compounds such as pyrimidines, benzimidazoles, phenylpropenamides, thiazolides, quinolines, 2 pyridones and sulfanilamides have achieved promising approach, and further research in this area may lead to more efficacious and safer anti-HBV drugs. In this review, these representative small synthetic heterocyclic molecules with potent anti-HBV activity will be discussed.