There are many methods for creating animal models of human genetic disease, and it is not possible for a short chapter to provide complete details of the methods used. There are four general approaches that will be discussed. One involves embryonic stem cells and another transgenic mice, each of which are the subject of major portions of other methods books (1 ,2 ). This chapter will provide only an overview of the general approaches and some specific details about several of them. Additionally, it provides references to primary papers or other review sources, in order to enable the investigator to find further details of the methods. Each of the methods has particular strengths and weaknesses, and a goal of this chapter is to help readers choose the approach that might be appropriate to their problem.