In the past 2 years the ability to successfully eradicate chronic HCV infection has been substantially enhanced by two landmark scientific breakthroughs. Firstly, the advent of HCV-specific direct-acting antiviral (DAA) compounds has resulted in a significant increase in sustained virological response rates in HCV genotype-1-infected treatment-naive patients and in non-responders to prior pegylated interferon and ribavirin therapy. Secondly, the identification of single nucleotide polymorphisms near the interleukin 28B (IL28B) gene that potently influence spontaneous and treatment-induced recovery from HCV infection has improved our understanding of hepatitis C pathogenesis, has helped spur the development of novel antiviral therapies and has provided a tool for pretreatment decision making in the context of genotype 1 HCV infection. In light of these advances, we review the interaction between these two discoveries and discuss the role of IL28B genotyping prior to treatment initiation in the context of both standard therapy and the newly approved DAA-based regimens. The role of IL28B genotyping is particularly relevant as DAAs are more expensive and carry a higher risk for anaemia and other drug-related side effects, while decision-making based on IL28B genotype may permit non-DAA-based treatment algorithms.