Although the unreliability and limitations of animal experimentation have increasingly been acknowledged, there remains a general confidence within much of the biomedical community that they can be overcome.7 However, three major conditions undermine this confidence and explain why animal experimentation, regardless of the disease category studied, fails to reliably inform human health: (1) the effects of the laboratory environment and other variables on study outcomes, (2) disparities between animal models of disease and human diseases, and (3) species differences in physiology and genetics. I argue for the critical importance of each of these conditions.