This review manuscript summarizes the available literature on animal studies dealing with the local and systemic effects of intramedullary (IM) reamed and unreamed nailing. It focuses on the question of whether the large numbers of studies have contributed to our clinical knowledge about its impact on perfusion, fracture healing, and about the clinical relevance of systemic side effects. The effects of IM contents that are squeezed out of the medullary canal into the venous and the systemic circulation due to reaming and nailing has been a major issue. In addition, the impact of the surgical procedure and the timing of such a major operation as femoral fractures surgery has been a major source of debate within the last decade. The compilation of relevant studies investigating the degree of impact of a surgical procedure and the influence of concomitant injuries depends on the design and the type of the animal model. If this fact is considered and if a model is selected that reflects the systemic impact comparable with the clinical situation, animal studies represent a valuable source of information. In this respect, fat embolization represents an additive surgical impact and can cause clinically relevant side effects if cofactors (e.g., thoracic trauma, severe shock, and polytrauma) are present that set the individual up for postoperative complications.