Abstract The spontaneous tendency of the hepatitis B virus (HBV) and hepatitis C virus (HCV) to mutate has led in both cases to the emergence of distinct viral genotypes with uneven geographic distributions. Numerous studies point to differential impacts of these genotypes on the course of chronic liver disease and response to treatment with currently approved drugs. HCV genotype plays a pivotal role in determining an individual's response to treatment. Evidence is also accumulating that HBV genotypes influence HBeAg seroconversion rates, the natural history and severity of chronic HBV liver disease, and the development of antiviral drug-resistance and precore/core promoter mutational patterns—all of which have an impact on disease prognosis and patient management. An overview of HBV and HCV genotypes, diagnostic methodologies for their determination, and the clinical relevance of genotypes for patient management is presented.