The use of model organisms is an integral part of the research approach in biomedical science, and more so after the genome of several animals was sequenced. However, the reliability of animal models (both conventional and genetically modified) in miming human pathologies as well as human response to drugs or environmental pollutants remains controversial. Additionally, recent advances confirmed major post-transcriptional and molecular mismatches between mice and humans during inflammation. Finally, even in basic research fields where model genomes are less controversially used, the results remain restricted to the models, making it challenging or impossible to extend results from the lab bench to the real world. In this talk we will list some classical philosophical problems regarding modeling and context reduction in general, and relate them to historical and recent controversial cases in medical research. Finally, we suggest that some institutional factors as well as the general scientific concern with objectivity and reproducibility discourage focus on the issue and thereby limit the search for relevant alternatives.