© 2017 Elsevier B.V. The ability of some viruses to establish latently infected chronic reservoirs that escape to immune control becomes a major roadblock that impedes the cure of these infections. Therefore, new alternatives are needed to pursuit the eradication of viral persistent infections. Gene silencing technologies are in constant evolution and provide an outstanding sequence specificity that allows targeting any coding sequence of interest. Here we provide an overview of the development of gene silencing technologies ranging from initially RNA interference to the recently developed CRISPR/Cas9 and their potential as new antiviral strategies focusing on the eradication of HIV.