Genome engineering has been enabled by programmable nucleases, including ZFNs, TALENs, and CRISPR/Cas9. Recently, a variety of Cas orthologs have been identified in diverse microorganisms, including type V Cas proteins and their ancestor, TnpB, expanding the genome-editing toolbox. These nucleases induce DNA double-strand breaks in a sequence-specific manner, which are subsequently repaired via either non-homologous end joining (NHEJ) or homology-directed repair (HDR) in living cells. These repair pathways are exploited for gene knockout or gene correction, respectively. In addition, base editing and prime editing technologies have been incorporated into the toolbox to enable precise genome modifications. These editing tools can be applied to generate model animals and plants with desired or improved traits, as well as to develop therapeutic strategies for gene therapy. In particular, genome editing can be combined with immune cell and stem cell technologies to treat cancer and genetic disorders. When applied to zygotes or germ cells, genome editing has the potential to cure hereditary genetic disorders; however, it also raises ethical concerns, such as its potential misuse for creating “designer babies.” Previously regarded as a static and unchangeable biological identity, the genome can now be corrected and modified at an unprecedented pace. While such genomic alterations were historically governed by evolutionary forces, they are now increasingly subject to intentional human design.