Hepatitis B virus (HBV) has an overwhelming distribution in the world and causes important human health problems. It has infected one-third of the global population and more than 350 million people are chronic carriers. Several aspects of HBV infection confer adaptive advantages that lead to a highly efficient dissemination of the virus through different routes of transmission. HBV genotypes and subgenotypes have been associated with differences in clinical and virological characteristics, indicating that they may play a role in the virus-host relationship. In particular, a clear association between genotype A and chronic outcomes in both children and adults depending on the subgenotype involved, and between genotype C and a higher risk of complications from HBV infection, has been demonstrated. Interestingly, subgenotype A2 and genotype C are respectively likely to predominate in high-risk groups for sexual transmission and in areas where perinatal transmission is the major mode of HBV dissemination. An evolutionary approach to HBV infection, based on the principles of natural selection, may offer explanations for how modes of transmission may favor some genotypes and subgenotypes over others and, ultimately, influence HBV virulence.