Pretreatment prediction of successful interferon-based therapy is less accurate than is prediction based on serum hepatitis C virus (HCV) RNA measurements taken during the first few weeks of therapy. Virological response, defined as loss of detectable virus RNA during the first weeks of treatment, identifies interferon-sensitive virus strains. Studies on viral decline kinetics have shown that interferon-based therapies produce a two-phase reduction in viral RNA levels. Sustained virological response is associated with rapid biphasic viral decline kinetics, resulting in elimination of virus from the blood within 4 to 12 weeks. Rapid viral elimination correlates positively with low incidence of relapse in end-of-treatment virological responders and is, therefore, an important parameter for determining duration or type of therapy. This article reviews the various patient and viral factors that help predict response to various interferon-based therapies, ranging from interferon alone to the new pegylated interferons.