The current standard-of-care treatment for chronic hepatitis C virus (HCV) infection, peginterferon plus ribavirin, results in a sustained virological response in 39-46% of genotype 1 patients, based on published reports and recently re-affirmed by findings in the IDEAL trial. While several directly targeted oral antiviral medications in development appear promising to decrease genotype 1 treatment failure, these agents are not yet approved for general clinical use, and their contribution to the management of relapsed or refractory HCV patients is uncertain. Other re-treatment approaches may include "watch and wait" or other strategies such as the use of consensus interferon plus ribavirin. Consensus interferon, a wholly synthetic interferon, was developed based on the most commonly represented amino acid sequence of the 14 different subtypes of interferon-alpha and has been shown in clinical trials to produce sustained virological responses in up to one-third of patients who do not respond to initial therapy and up to 50% of those that relapse after treatment with peginterferon plus ribavirin. In this monograph, the benefits and challenges of each of these available and future treatment options will be discussed with an eye toward optimizing therapy for an individual patient.