The widespread availability of injectable therapies and increase in illicit injection drug use were responsible for the rapid emergence of hepatitis C virus (HCV) infection in the latter half of the 20th century. Iatrogenic exposures and illicit injection drug use have been the predominant risk factors for HCV transmission worldwide. In developing countries, unsafe therapeutic injection practices appear to be responsible for most infections. In developed countries, donor testing has virtually eliminated transfusion-related infections, but infections transmitted to patients by unsafe injections practices is an emerging problem. Injection drug use is the major risk factor for HCV; incidence remains high among new injectors, and this behavior likely contributes to and/or confounds reported associations between HCV-positive persons and histories of noninjection drug use, tattooing, and incarceration. Increased use of illegal drugs also may play a role in the emergence of sexually transmitted HCV infections among HIV-positive men who have sex with men. Ongoing monitoring of the epidemiology of HCV infection is crucial for preventing future infections.