The mainstay of treatment of chronic hepatitis C is pegylated interferon combined with ribavirin and more than 50% of naïve patients will have viral cure with either 6 months (genotypes 2 and 3) or 12 months (genotypes 1,4, and 6) with the initial treatment. However, populations have been defined that respond less well to routine treatment including African Americans, immune suppressed populations, obese patients and cirrhotic patients. These types of patients are enriched in groups of patients who are non-responders to treatment. This article discusses viral kinetics that may impact treatment response, strategies to maximize treatment effectiveness in these populations and the treatment of non-responders in general. Early viral kinetics can be used to define response or non-response and these results can be used to modify subsequent treatment length and dose.