Late in 2009 and early 2010, 4 landmark studies appeared in the scientific literature reporting the association between some host genetic polymorphisms and the odds of hepatitis C virus (HCV) eradication, both spontaneous and treatment-induced. The impact of this watershed discovery is hard to overlook—for several reasons. First, the statistical significance of the association was unprecedented, thus making the risk of a haphazard or artifactual finding very unlikely: ever since the first reports were published, several groups have independently confirmed, and more will certainly continue to do so, this striking association. Second, the polymorphisms were linked to a gene encoding for interleukin-28B (IL28B), a cytokine involved in the innate immune response: as a result, this association was utterly plausible. Third, the polymorphisms near the IL28B gene have not only been associated with therapy-induced HCV eradication in other settings, such as among patients coinfected with the human immunodeficiency virus or after liver transplantation, but also with a number of additional, distinct HCV outcomes, such as severity of acute hepatitis, inflammatory activity of chronic hepatitis, liver disease progression, liver steatosis, and cholesterol levels. All in all, the discovery of the predictive value of IL28B polymorphisms has paved the way to not only new drug development, but to innumerable research avenues. One of the major challenges will be unravelling the details of the mechanistic link between IL28B and the eradication of HCV: as of today, this link remains elusive, baffling the world-class investigators who have focused their efforts for more than 2 years on this issue, so far to no avail. In contrast, it will be crucial to define with sufficient precision the appropriate application of this genetic assay to the clinical arena, ideally through prospective studies. This issue of Hot Topics in Viral Hepatitis contains articles by two of the leading experts in the field who took part in the above discovery: Salim Khakoo from the Imperial College, London, and Jacob George from the University of Sydney, whom I thank wholeheartedly for having accepted the task of summarizing in a few pages all the most important data surrounding the intricate relationship between host gene variations and HCV outcomes. The articles are preceded by a summary of the abstracts on IL28B presented at the recent Annual Meeting of the European Association for the Study of the Liver held in Berlin.