At least ten hepatitis B virus (HBV) genotypes (A to J) with distinct geographic distributions have been recognized. HBV genotype is not only predictive of clinical outcome but also implicated in responsiveness to antiviral therapy, especially interferon-based regimens. HBV genotype-specific immunologic and virological pathogenesis may contribute to heterogeneous clinical outcomes in chronic hepatitis B patients. For example, patients with genotypes C and D infection have a lower rate of spontaneous HBeAg seroconversion. In addition, genotype C and D have a higher frequency of basal core promoter A1762T/G1764A mutation than genotype A and B. Genotypes C and D also carry a higher risk of cirrhosis and HCC development than genotype A and B. Therapeutically, genotype A and B patients have a better response to interferon-based therapy than genotypes C and D patients, but the response to nucleos(t)ide analogues is comparable across all HBV genotypes. In conclusion, genotyping of HBV can help practicing physicians identify chronic hepatitis B patients who are at risk of disease progression and optimize anti-viral therapy in clinical practice. © 2013 Springer Science+Business Media New York.