Exploring the potential of TFOs coupled to DNA damaging agents to induce homologous recombination (HR) for gene correction from The past and presence of gene targeting: from chemicals and DNA via proteins to RNA GeelT. M. RuitersM. H. J. CoolR. H. HalvicL. VoshartD. C. Andrade RuizL. Niezen-KoningK. E. ArimondoP. B. RotsM. G. 2018 The ability to target DNA specifically at any given position within the genome allows many intriguing possibilities and has inspired scientists for decades. Early gene targeting efforts exploited chemicals or DNA oligonucleotides to interfere with the DNA at a given location in order to inactivate a gene or to correct mutations. We here describe an example towards correcting a genetic mutation underlying Pompe's disease using an oligo-fused nuclease (TFO-MunI). In addition to the promise of gene correction, scientists soon realized that genes could be inactivated or even re-activated without inducing potentially harmful DNA damage by targeting transcriptional modulators to a particular gene. First generation programmable DNA binding agents, however, proved difficult to fuse protein effector domains to. The engineering of gene-targeting proteins (ZFPs, TALEs) circumvented this problem. The disadvantage of protein-based gene targeting is that for every locus a fusion protein needs to be engineered. The recent introduction of CRISPR/Cas offers a flexible approach to target a (fusion) protein to the locus of interest using cheap designer RNA molecules. Many research groups now exploit this platform and the first human clinical trials have been initiated: CRISPR/Cas has kicked off a new era of gene targeting and is revolutionizing biomedical sciences.This article is part of the discussion meeting issue ‘Frontiers in epigenetic chemical biology’.