Segmental bone defects (SBD) are difficult to treat, requiring a comprehensive understanding of the bone and soft tissue injury. Defect size, fracture characteristics, and local and systemic biology all help dictate treatment options. Bone grafting with autograft or allograft, Masquelet technique, and bone transport with external or internal fixation can all be used successfully in the correct patient. When deciding on the best treatment option and addressing any complications throughout the process, it is important to always keep in mind the three principles of bone healing: sterility, stability, and biology. The goal of this review is to present the history of treatment for critical SBD, including the indications and challenges that have been addressed and current and emerging treatment options.