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There is clinical evidence that patient‐specific comorbidities like osteoporosis, concomitant tissue injury, and ischemia may strongly interfere with bone regeneration. However, underlying mechanisms are still unclear. To study these mechanisms in detail, appropriate animal models are needed. For decades, bone healing has been studied in large animals, including dogs, rabbits, pigs, or sheep. However, large animal models display a limited ability to study molecular pathways and cellular functions. Therefore in recent years, mice and rats have become increasingly popular as a model organism for fracture healing research due to the availability of molecular analysis tools and transgenic models. Both large and small animals can be used to study comorbidities and risk factors, modelling the human clinical situation. However, attention has to be paid when choosing an appropriate model due to species differences between large animals, rodents, and humans. This review focuses on large and small animal models for the common comorbidities ischemic injury/reduced vascularization, osteoporosis, and polytrauma, and critically discusses the translational and molecular aspects of these models. Here, we review material which was presented at the workshop "Animal Models of Comorbidities in Fracture Healing Research" at the 2019 ORS Annual Meeting in Austin Texas. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2491–2498, 2019 [ABSTRACT FROM AUTHOR]