Hepatitis C virus genotype 4 (HCV-G4) is prevalent in the Middle East and Africa and has spread to several regions in Europe. HCV-G4 represents a major health problem in Egypt, with a prevalence rate of 13%. Recently, HCV-G4 has been spreading in Europe particularly among intravenous drug users (IDU) populations, who represent the main reservoir for HCV in Europe. This article reviews the current therapeutic strategies for HCV-G4 infections in different populations. HCV-G4 has been considered a difficult-to-treat genotype because of the poor sustained virological response (SVR) rates reported with a conventional interferon (IFN)-based regimen. Pegylated IFN and ribavirin combination therapy was associated with significant improvements in SVR rates that currently exceed 60%, particularly with individualized therapy. Lower response rates have been reported in specific situations, namely chronic HCV-G4 infection in IDUs and patients co-infected with human immunodeficiency virus (HIV). Rapid and early virological responses have been useful tools for determination of the duration of therapy. In conclusion: therapy of HCV-G4 has shown significant improvements, with higher sustained response rates and possibilities for a shorter duration. More research is required to optimize therapy in special populations such as IDUs and HIV-co-infected patients.