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During the last half-century pathologists have explored the biologic mechanisms associated with inherited human and veterinary diseases by using inbred and inbred mutant (spontaneous) strains of mice. The first successful gene transfer to mice by pronuclear injection of the herpes simplex virus thymidine kinase gene and rabbit and human beta-globulin genes was achieved in the early 1980s. This accomplishment was followed a few years later with the creation of a mouse bearing a disrupted hypoxanthine phosphoribosyl transferase (hrpt) gene (targeted mutation based on ES cell blastocyst injection). Since then, hundreds of genetically engineered models of biomedical importance have been created. The unprecedented scale and scope of development of engineered models present great opportunities as well as experimental challenges to the investigator. The aim of the present review is to provide a framework of information on engineered mouse models from the perspective of experimental and comparative pathology research. Sections include: 1) a brief historical account of the development of mouse models of disease, with increasing progression of genetic refinement as represented by inbred (spontaneous) and congenic (targeted) mutant strains of mice; 2) a synopsis of spontaneous and targeted mutations, with anecdotal examples of expression of individual genes and interactions between multiple mutant genes; 3) selected examples of targeted mutations of interest to developmental and cancer biologists and immunologists; 4) an overview of the technology of development of transgenic mice; and 5) an introduction to on-line database resources of current multi-species genomic information.