Animal models are a fundamental tool in the life sciences. They have advantages and disadvantages compared with other approaches. In a few instances, they represent the only reasonable approach. However, increasingly modern methods allow the 3R principle of reducing, refining and replacing animal experiments to be put into practice, as required wherever possible by European legislation. This article summarizes limitations typical of animal models. However, this does not mean that each and every limitation holds true for all animal models and that its alternatives have fewer limitations. A serious assessment of the models used is necessary to draw conclusions and make decisions in an evidence-based manner. Only by assessing the performance characteristics of any tool used in research, the results can be interpreted and the method employed can be complemented properly.