The repertoire of nuclease-guided genome modifications was recently expanded to include homology-independent targeted integration (HITI) of exogenous DNA by a report published in the December 2016 issue of Nature (Suzuki et al. 2016). The key feature distinguishing HITI from homology-based DNA Knock-in is its applicability in post-mitotic cells of non-regenerative tissues, such as the brain and retina. Suzuki et al. demonstrated the therapeutic utility of HITI through genomic knock-in of an exon previously deleted by a naturally occurring mutation that causes blindness in rats. The potential therapeutic impacts are farther-reaching than the replacement of deleted genomic segments. Targeted integration of therapeutic genes in post-mitotic cells in vivo may improve treatments that rely on continued gene augmentation or silencing.