Abstract: Hepatitis B virus infection is a major public health problem worldwide especially in East Asia. The viral infection, if persistent, may lead to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. In1998, FDA approved GlascoSmithKline's Epivir-HBV (Lamivudine), a small molecule drug that inhibits HBV DNA polymerase and interferes with viral replication. Since then, a few similar drugs have been approved and many candidates are currently at preclinical and clinical development. The use of small molecular drugs that target HBV DNA polymerase is a milestone in the treatment of chronic hepatitis B. In this review, we will focus on HBV DNA polymerase and discuss the preclinical and clinical development process for the HBV polymerase inhibitors. The DNA polymerase mutants associated with drug resistance will also be discussed. The mechanism of the drug resistance and further understanding of these DNA polymerase inhibitors may help the determination of better clinical regimen for HBV therapy and patient care.