Genome editing is now a routine procedure in many mammalian genetics laboratories. The ostensibly short but intense history of genome-editing approaches illustrates how a disruptive technology can universally colonize a field when this new methodology, conceived to alter mammalian genomes at specific locations, is found to efficiently and robustly deliver results. This review summarizes the early development of genome editing using nucleases, from the pioneering experiments using yeast meganucleases, to the latest prokaryotic nucleases used for precise genome manipulation. Gene-editing nucleases belong to one of three known categories: zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN), and clustered regularly interspaced short palindromic repeats (CRISPR) and their associated proteins (Cas) tools. All operate on the same principle; they are all capable of inducing a double-strand break (DSB) at a defined genomic sequence that is subsequently corrected by endogenous DNA repair mechanisms. DSBs can be repaired through non-homologous end joining (NHEJ), resulting in small insertions and/or deletions (INDELs) and, hence, often leading to gene disruption. Alternatively, DSBs can be repaired through homology-driven repair (HDR), in the presence of donor homologous DNA sequences, resulting in gene-editing events.