New genetic models provide better biological mimics of human tumors. The new models can give deeper insight into tumorigenesis and provide better targets for testing therapies. To use the new models most successfully, it is useful to keep in mind limitations that are harder to overcome by genetic manipulation. These include biochemical and anatomical differences between species, as well as differences in scale, both spatial and temporal. Three approaches to new genetic brain tumor models are described in the following articles. This essay provides a context, bringing out both advantages and remaining concerns. Examples are taken from work in brain tumor immunobiology and immunotherapy. The complementarity of different models, and the dichotomy between general principles and model-specific details are stressed.