The introduction of new agents and regimens for the treatment of chronic hepatitis C, such as pegylated interferons and combination therapy with ribavirin, has resulted in substantial improvements in sustained virologic response rates. However, treatment remains a challenge, particularly for certain patient populations, because several virus-related and patient-related factors are associated with a lower virologic response to therapy. Hepatitis C virus genotype 1 and a high baseline viral load are the major viral factors associated with lower response. Patient-related factors include previous relapse or nonresponse to treatment, the presence of cirrhosis, African-American ethnicity, older age, contraindications to treatment, and obesity. This article reviews the data on interferon-based therapies among patients with lower chances for sustained virologic response and discusses the potential of the new pegylated interferons.