Mouse models of human cancer are valuable tools for cancer research. Although xenografts and genetically engineered models (GEMs) possess limitations as well as advantages, each system plays a significant role in preclinical testing. Tumor xenografts are easy to use, relatively inexpensive, and reproducible. The main drawback of xenografts is that the genetics and histology of the tumors are frequently not representative of the respective human tumor and, thus far, these models have not been as predictive of therapeutic success as one would like. By contrast, GEMs are histologically and genetically accurate models of human cancer but have disadvantages of heterogeneity with regard to frequency, latency, and growth. These disadvantages are reminiscent of the variable behavior of actual human tumors. Recently, these shortcomings have been partly overcome with the development of anatomic and molecular in vivo imaging techniques such as magnetic resonance imaging and bioluminescence imaging. These new technologies will hopefully support the use of GEMs in preclinical trials and help determine if trials in GEMs are more predicative than xenografts of human responses.