Genetically engineered rodent models have become an essential tool for understanding of gene functions in the whole organism, for unraveling disease etiology and pathogenesis, and for preclinical testing of diagnostic, preventive and therapeutic approaches. Clinically-relevant successful animal models are expected to have properties common with human disease, such as pathological features, molecular mechanisms, course of disease progression, competent immune system, and involvement of identical cell lineages and tissues. Accurate identification and validation of such properties requires comprehensive phenotyping, which, to a large extent, is based on extensive knowledge of pathology, a discipline that studies causes and mechanisms of a disease. Pathologists are medical professionals who are trained in the integration of clinical presentation of disease with associated structural and functional changes in the whole organism, as well as in its component organs, tissues, cells and molecules. Unfortunately, the predominant majority of animal modelers are insufficiently prepared for interactions with pathologists. In fact, few principal investigators and members of their laboratories have adequate understanding of principles and methods of pathology, and some even do not recognize the key role of a pathologist in comprehensive animal phenotyping. Another major limiting factor in efficient validation of murine models for human disease has been inadequate number of human and veterinary pathologists sufficiently trained in rodent pathology. Further complicating situation, some diagnostic pathologists do not have appropriate knowledge of contemporary biomedical research, thereby endangering the efficacy of their communications with investigators. During recent decade these shortcomings have begun to attract increasing attention, and some solutions, such as workshops and courses, have been developed. However, the situation remains far from optimal and requires additional measures, such as inclusion of basic histology and pathology subjects into graduate school curricula, focused facilitation of human and veterinary pathologists’ training in murine pathology, and active promotion of authentic collaborations between animal modelers and diagnostic pathologists. Success of such activities should ensure that comprehensive phenotyping of genetically engineered rodents will become truly efficient research tool entirely satisfying the needs of rapidly developing biomedical research.