The first germline transmission-capable transgenic mice were developed in the early 1980s in the laboratories of Frank Ruddle (Yale), Ralph Brinster (University of Pennsylvania), and Richard Palmiter (University of Washington). Since these pioneering experiments, multiple techniques have been developed to generate genetically engineered mice and rats. Each has advantages and drawbacks, making each one more or less appropriate for particular types of model generation projects and study objectives. The following review by Caroline Horizny at Taconic Biosciences will highlight the basics of each genome modification method, as well as outline some of the pros and cons of each.