Hepatitis B virus (HBV) has been classified into 10 genotypes (A–J) according to genome sequence divergence. HBV genotypes have a distinct geographical distribution. As chronic HBV infection is endemic in the Asian region, genotypes B and C prevail there, and genotypes A and D are mainly found in the western world and Europe. Genotypes A, B, C, and D have been studied most extensively. In Europe and Asia, most patients with genotypes A and B have acute hepatitis B; however, some mutants may tend to cause fulminant hepatitis B. Many studies have indicated that the severity and outcomes of chronic hepatitis B infections are more serious in patients with genotypes C and D than in those with genotypes A and B. Cirrhosis and hepatocellular carcinoma (HCC) are more frequently diagnosed in carriers of genotypes C and D than in those of genotypes A and B. Accumulating evidence indicated that higher plasma HBV DNA levels, infection with HBV genotype C, as well as mutations at 1653T, 1753V, and A1762T/G1764A are independently associated with the risk of HCC in Asian men. However, the therapeutic responses differ with regard to the different HBV genotypes. For example, the response to interferon-α treatment in patients with genotypes A and B was better than that in patients with genotypes C, D, and mixed genotypes. Some studies have shown seroconversion after treatment, i.e., genotypes A and C may switch to genotypes D and B, respectively. Some reports indicated a correlation between the emergence of the hepatitis B e antigen-negative variant in patients with genotypes C and D and worsening of liver injury without sustained response. In order to provide better treatment options for these poorly responding patients, further studies, e.g, novel immunomodulatory therapies, are required. Many studies have shown that HBV genotypes have remarkable clinical and epidemical differences; however, HBV sub-genotypes, mixed genotype infections, and the effect of different genotypes on the treatment of HBV infections require further studies.