Clinical observations are usually critical to success in finding a genetically engineered mouse (GEM) phenotype. The key items include embryonic phenotypes, beginning in late gestation and working back to earlier developmental time points. Perinatal and infantile phenotypes look for failure to thrive, loss of weight, and difficulty breathing. Adult phenotypes,to see if pup normal at weaning, reproductively normaland further age-related lesions. The neurological phenotypes depend on the results of behavior tests. Some clinical chemistry and hematology may prove useful in certain cases. Gross pathologic phenotyping includes the method of euthanasia, gross observations, dissection and fixation, and necropsy procedure. The basic histopathological phenotyping includes interpretation of ten to eleven slides and forty tissues. Here we will introduce the concept of pathologic phenotyping and also report standardized mice necropsy,interpretation and morphological diagnosis of gross pathology and histopathology, histological tissue trimming, immunohistochemical (IHC) labelling, histochemical (HC) staining and embryo pathologic phenotyping as well. A few problems with pathological interpretation of experimental study, wrong diagnosis in published paper, and how to differentiate between from infectious diseases, spontaneous background disease to the pathological phenotypes will be reported as well.