The ability to engraft human tumors and human immunocompetent cells successfully in severe combined immunodeficient (SCID) mice has spawned the development and use of human-mouse chimeric models to evaluate anti-cancer therapies. The lack of standardization and many other potential pitfalls have contributed to the current controversy surrounding the reliability of these different models. Five frequently used SCID mouse models and their specific applications are summarized with the specific aim of providing an objective discussion of the strengths and limitations of each model, together with suggestions for overcoming some of the variabilities and for improving the design and use of future models.