During hepatitis B virus (HBV) infection, selection and takeover of mutant viruses are frequent events driven by both humoral and cellular host-immune response and antiviral therapy. Therefore, dynamic studies of the variations of viral mutants over time within the overall viral population in relation with the host-virus interactions are extremely important to better understand the biological and pathogenic role of each mutant. With these premises, we review the more frequent mutations detected in each of the 4 open reading frames of HBV. A detailed analysis of the pathobiologic implications of pre-C region mutations which suppress the expression of the hepatitis B ‘e’ antigen, will be presented, as these mutations induce a specific change in virus biology and the variations of the ratio between wild-type and mutant correlate with significant events in host-virus interactions.