A great deal of information on the molecular heterogeneity of hepatitis C virus (HCV) has been achieved since its discovery in 1989. However, little is known about the clinical significance of these variations. Based on the degree of sequence variation, HCV has been classified into six major groups or types, differing by 31-34% at the nucleotide level over the entire virus genome. Each type is divided into several subtypes that differ by 20-23% in nucleotide sequence. Viruses within the same subtype are up to 10% divergent and, within infected individuals, vary by up to 1.5%. Genotype distributions are not homogeneous around the world and may reflect both historical and recent parenteral routes of transmission. The clinical implication of these genomic variations are not yet fully elucidated: genotype 1b has been associated with end-stage liver disease, including liver cirrhosis and hepatocellular carcinoma, but this finding might rather reflect its earlier introduction to the populations studied. Consistent evidence exists that types 2 and 3 have a higher response rate to interferon treatment than type 1, although the interplay between genotype and viral load in determining the response is still unclear. Immunohistochemical studies indicate a stronger activation of the endogenous interferon system in the liver of patients infected with type 1 compared to those infected with types 2 and 3, explaining, at least in part, its low responsiveness to exogenous interferon treatment. Biological, sequence-dependent variations of genotypes have been poorly investigated to date, but differential efficiency of translation activity of the 5' non-coding region has been reported. The availability of "in vitro" systems for evaluating pathogenetic aspects and neutralization mechanisms will improve the present knowledge on this world-wide infectious disease and on the clinical usefulness of distinguishing between genotypes.