Although the rat is a preferred model in many fields of biomedical sciences, the inability to generate germline competent embryonic stem (ES) cells was a major drawback for research activities that aimed to elucidate gene functions. Several alternative strategies like N-ethyl-N-nitrosourea (ENU) or transposon-mediated mutagenesis were developed successfully for this species. Countless experiments in many laboratories around the world were undertaken to overcome this problem. Eventually, the successful establishment of rat ES cells and rat-induced pluripotent stem (iPS) cells was reported, 27 years after the first reported generation of mouse ES cells. Furthermore, the application of zinc-finger nucleases (ZFNs) to early-stage rat embryos demonstrated effectively that another way existed for generating knockout rats. ZFNs require only the standard techniques that are used to produce transgenic animals and are expected to comprise a major tool for the gene-targeted generation of knockout animals. These newly developed tools, in conjunction with the solid basis of the rat in the area of physiological and behavioral experiments, will not only close the gap between the rat and the mouse as the mammalian genetic model of choice, but also boost the significance of the rat as a model animal in research laboratories around the globe.