Hepatitis C virus (HCV) is a single-stranded RNA virus known for its high genetic variability owing to the lack of a proofreading mechanism of its RNA dependent RNA polymerase. Until now, numerous studies have been undertaken to clarify the correlation between pretreatment HCV genetic variability and the therapeutic response. Even with the recent combination therapy of peginterferon plus ribavirin for chronic hepatitis C, viral response is variable, and only half of treated patients could clear the virus [sustained viral response (SVR)]. In this review, the contribution of viral genetic variability affecting the treatment outcome is discussed according to each HCV genomic region.