Hepatitis B virus (HBV) tends to mutate easily due to its special structure and life cycle. Mutation changes the biological behavior of HBV and its sensitivity to antiviral drugs and even affects therapeutic effect and accelerate disease progression. The point mutations are commonly see in the pre-S/S open reading frame (ORF), which may be associated with immune escape and occult HBV infection. The G1896A mutation is often observed in the pre-C/C-ORF and is associated with the development of HBeAg-negative chronic hepatitis B (CHB), hepatocellular carcinoma (HCC), and severe chronic hepatitis (liver failure). The mutations in P-ORF mainly occur in the reverse transcriptase (RT) domain and are closely related to the resistance to nucleos(t)ide analogues. The A1762T and G1764A mutations occur in the basal core promoter (BCP), which overlaps with X-ORF, and may be associated with HBeAg-negative CHB, HCC, and severe chronic hepatitis (liver failure). Clarification of the association between these mutations and diseases helps to develop tailor-made diagnostic and therapeutic regimens for patients with HBV infection.