Numerous murine models have been developed to study human cancer. These models are used to investigate the factors involved in malignant transformation, invasion and metastasis, as well as to examine response to therapy. One of the most widely used models is the human tumor xenograft. In this model, human tumor cells are transplanted, either under the skin or into the organ type in which the tumor originated, into immunocompromised mice that do not reject human cells. For example, the xenograft will be readily accepted by athymic nude mice, severely compromised immunodeficient (SCID) mice, or other immunocompromised mice (Morton and Houghton, 2007). Depending upon the number of cells injected, or the size of the tumor transplanted, the tumor will develop over 1-8 weeks (or in some instances 1-4 months, or longer), and the response to appropriate therapeutic regimes can be studied in vivo. Another type of animal model for studying human cancer is the genetically engineered mouse (GEM) model. The genetic profile of these mice is altered such that one or several genes thought to be involved in transformation or malignancy are mutated, deleted or overexpressed; subsequently, the effect of altering these genes is studied over time and therapeutic responses to these tumors may be followed in vivo. Both athymic nude mice and mouse xenograft models that use human tumor cell lines have been used for decades to increase our understanding of factors affecting tumor growth; however, recent information regarding the key influence of the tumor microenvironment on tumor progression and growth has led to greater reliance on GEM tumor models using immunocompetent mice, as well as use of primary human tumor xenografts in humanized mouse models. In fact, the xenograft models are often regarded as inferior to the GEM models. In this article, I hope to show that each model has its use in cancer diagnostics and in preclinical therapeutic modalities. Several criteria have recently been suggested for GEM models of human cancers:(1) mice must carry the same mutation that occurs in human tumors;(2) mutations should be engineered within the endogenous locus, and not expressed as a transgene;(3) mutated genes should be silent during embryogenesis and early postnatal development, except for in models of inherited pediatric tumors;(4) mutations should be within the specific target tissues in selected cell types; and (5) mutations must occur in a limited number of cells. Additional ‘desired features’ are that the tumor type and anatomopathology should be as similar as possible to that observed in human tumors, and that tumor development should proceed through the same, or similar,‘preneoplastic’stages (M. Barbacid, Keystone Symposium on Inflamation, Microenvironment and Cancer, 2008, and personal communication). Another important criterion, which is difficult to achieve in GEM models, is that the host/tumor environment should be reproducible in the model. Moreover, although mouse tumor models using GEM are highly useful for evaluating the effects of specific mutation, deletion or gene amplification of one or two genes during murine tumor progression, they usually cannot fully reproduce the genetic complexity of human tumors. For example, in humans, malignant melanomas and other tumor types with similar degrees of genetic heterogeneity exhibit an extensive degree of aneuploidy, and the specific gain or loss of genes varies enormously from one cell to another within the same tumor. Thus,