Hepatitis C virus (HCV) is distributed globally, affecting all countries. The majority of new HCV infections in developed countries are due currently to needle sharing by those engaging in intravenous drug use (IDU) and nosocomial patient-to-patient transmissions in healthcare settings. In developing countries, blood transfusion remains a major cause, followed by transmission by medical procedures, especially those using contaminated injection equipment, and IDU. The large reservoir of asymptomatic chronically infected individuals, the fluxes of immigration from endemic areas to less prevalent regions, and the uncontrolled epidemic of IDU continue to spread HCV throughout the world. The goal of this chapter is to review the substantial changes in HCV transmission routes of groups at risk of HCV infection, genotype distribution, and prevalence in the general population. The data describe a worldwide HCV prevalence of 2.27%, or 160 million persons infected with this virus. HCV prevalence and transmission routes are the basis for the development of measures to prevent new infections, initiate HCV screening and early treatment, reduce complications associated with HCV infection, and attenuate the huge socioeconomic impact associated with HCV infection.