A significant increase in understanding the host genetic determinants of susceptibility to viral infections have been obtained in the last years. Recently, two single nucleotide polymorphisms (SNPs) rs12979860 (T/C) and rs8099917 (T/G), upstream of the interleukin (IL) 28B/interferon (IFN) lambda 3 (λ3) gene have been clearly associated with spontaneous and treatment-induced viral clearance in hepatitis C (HCV) infection. Due to its strong power in predicting response to IFN/ribavirin therapy the above SNPs has been used as diagnostic tool even their relevance in the management of HCV infection is probably intended to be blunt in the era of IFN-free regimens.The recent discovery of new genetic variant ss469415590 TT/ΔG upstream of IL28B, which generates the novel IFN lambda 4 (λ4) protein has opened up a new and alternative scenario to understand the functional architecture of type III IFN genomic regions and to improve the knowledge on the pathogenetic mechanism of HCV infection. A role of ss469415590 in predicting responsiveness to antiviral therapy has been al so observed in HCV infected patients receiving direct antiviral agents (DAAs) .The underlying biologic mechanism which links the above IL28B polymorphisms (in both IFNλ3 and IFNλ4 genes) to spontaneous and treatment-induced clearance of HCV infection basically remains to be discovered. Despite this, the possibility of make a small glimmer of light on this issue, which represents the main aim of this review, may provide new insights into the general topic “host genetics and viral infections” .This article is protected by copyright. All rights reserved.