Infection with hepatitis C virus (HCV) is a major global health issue. Only a small proportion of patients clear the virus spontaneously and the majority develop chronic hepatitis C infection. Chronic hepatitis C is one of the most common causes of advanced liver disease in the western world and is now the leading indication for liver transplantation. Unfortunately, the standard treatment, consisting of pegylated-interferon and ribavirin, is suboptimal. Less than 50 of patients infected with HCV genotype 1 are cured, treatment is costly and is associated with significant toxicity. Therefore, there has been a need to identify accurate predictors of treatment outcome to facilitate treatment decision-making. Four independent genome-wide association studies have recently confirmed an association between genetic variation in the region of the IL28B gene and treatment outcome in HCV-1 patients. Patients who carry the good response variant are two- to three-fold more likely to be cured. The difference in the frequency of the good response variant between patients of different ethnic background explains much of the recognized ethnic disparity in treatment response rates. The IL28B variants are also associated with likelihood of spontaneous clearance of HCV infection. This discovery represents a significant advance in our ability to personalize HCV therapy, as well as suggesting novel avenues for research into viral pathogenesis and therapeutic development.