Hepatitis B virus (HBV) infects 250 million people worldwide, resulting in nearly one million deaths annually. HBV reactivation due to persistence of HBV genomic reservoirs is the major clinical limitation for currently available anti-HBV agents. There is a need, therefore, for understanding persistence mechanisms of HBV and to develop novel antiviral agents against HBV. Computational biology approaches like homology modeling, molecular dynamics and bioinformatics are being employed in recent years to understand the mutations of drug resistance and persistence in HBV and to study the DNA and RNA protein sequences of viruses. In the present review we discuss recent studies on discovery of anti-HBV agents using these computational approaches.