It is estimated that there are 4.0 million individuals chronically infected with Hepatitis C virus (HCV) in the US. Due to the slow progression of disease, the incidence of HCV has declined in the last two decades. However, it is anticipated that the number of individuals requiring treatment for liver disease associated with HCV will increase for years to come. Until 2011, HCV genotype 1 infections were treated with 48 weeks of pegylated interferon and ribavirin combination therapy; only 50% of patients had a successful outcome. Moreover, patients often withdraw from treatment prematurely because of the high cost and adverse effects of therapy. All of these factors make HCV infection a serious healthcare issue. Recent advances in HCV management include the discovery of host genetic polymorphisms that can predict treatment outcome, as well as the availability of the first direct acting antiviral agents that promise to revolutionize HCV management and increase the likelihood of a favorable treatment outcome. In 2009, multiple independent groups performed genome-wide association studies in HCV infected individuals and identified several single-nucleotide polymorphisms (SNPs) near the IL28B gene that predict the likelihood of both spontaneous and treatment-induced HCV clearance. This article provides an overview of the genome-wide association studies that uncovered the role of the IL28B genotype and reviews the clinical utility of IL28B genotyping.