Orthopedic fracture surgery has made significant advances in recent years, but large segmental bone defects remain a significant clinical problem. While surgical techniques have been developed or modified to address these issues, challenges remain. Further, to effectively address this issue, a suitable path from the benchtop to the clinic must be established. This is most commonly done using large animal models, which provide the opportunity to test different treatment options. This is certainly more complicated than it appears, as various anatomic and physiologic differences can produce complications not normally seen in humans. For this reason, proper species and bone selection is critically important.Here we review the current experimental methods, types of internal and external fixation, and large animal models used in segmental bone defect studies conducted in weightbearing long bones. This review will also provide insight into the efficacy of hardware fixation strategies and the translatability of said strategies into clinical practice.