The objective of this talk is to inspire preclinical researchers to “think out of the box” in their selection of research animals and not limit their perspective to the sole use of traditional animal models, but rather select a model that is most appropriate for the question of interest.Preclinical research relies heavily on the use of traditional research animals such as mouse, rat, guinea pig, rabbit, dog, pig, sheep, etc. and a wide array of associated disease models. The benefit of this approach is well-characterized models on both a genetic, anatomical and physiological level that share a mammalian ancestry with humans. However, in some cases there exist untraditional research animals that are much more suited to study specific preclinical or basic biological phenomena. This is formulated in the August Krogh Principle: “For a large number of problems there will be some animal of choice or a few such animals on which it can be most conveniently studied” (Krogh, 1929). This also applies to a number of MRI experiments in which the use of unusual animal models is justified because of certain capabilities in the animal that cannot be mimicked in more traditional research animals.In this talk, three cases will be presented in which we have applied unusual animals in preclinical studies. The first case is in the investigation of regenerative mechanisms in the Mexican axolotl, a salamander widely applied in regenerative medicine due to an impressive and unsurpassed ability to regenerate tissue in a wide array of organs and tissues such as cardiac tissue, intestines, liver, skeletal muscle, central and peripheral nervous system, lens, retina, jaw, and even whole appendages such as limbs and tail (Stoick-Cooper et al, 2007). We have applied MRI to monitor cardiac function during complete regeneration of a cryoinjury affecting 45% of the ventricular myocardium in the axolotl. Additionally, we have used MRI to track stem-like cells labelled with super paramagnetic iron oxide nanoparticles (SPIOs) in the regenerating limb of the axolotl. Both experiments would be inapplicable with the use of traditional mammalian research animals due to the general lack of regenerative potential in this class. In the second case we have applied MRI to non-invasively monitor the phenotypical flexibility of visceral organs during digestion after prolonging fasting in pythons. In contrary to humans and most other mammals that do not have the ability to quickly upregulate their digestive system when exposed to a large meal after prolonged famine caused by catastrophic events or anorexia, pythons have the ability quickly upregulate both size and function of their visceral organs after several months of fasting to accommodate to a meal up to 25% of their body mass. In the third case we assessed the metabolism in the rodent placenta using hyperpolarized MRI. To circumvent the obstacle of multiple and minute fetuses found in most traditional rodent models (such as mouse and rat) we applied the chinchilla characterized by producing only a single and relatively large cup per pregnancy. Finally, we have applied MRI to investigate physiological mechanisms related to more basic life science questions. I will briefly discuss how we have applied MRI to investigate the sound producing apparatus in toothed whales (Wisniewska et al 2015) and digestion mechanisms in large tarantulas (Lauridsen et al 2011).Changing from well characterized research animals to more unusual species is not without obstacles in MRI experiments. Unusual research animals may require other types of anesthesia than usually applied, and as MRI is often incompatible with easy access to the animal specific anesthesia protocols needs to be developed in advance. Additionally, anatomical recognition can be challenging in species not well known and physiological data may need careful interpretation in the case of no reference values. These obstacles should be assessed against the potential benefits of selecting an untraditional research animal. However, if the scientific question of interest points to the use of unusual animal models these should not be disregarded but rather welcomed as a professional challenge.