Bone defects, which often arise from high-energy injuries, infections, tumor resections, or nonunions, represent a persistent challenge in orthopedic trauma surgery. Autologous bone grafting remains the gold standard due to its unique combination of osteogenic, osteoinductive, and osteoconductive properties. However, issues such as donor site morbidity, limited graft volume, and increased surgical time have driven the development of bone graft substitutes. These substitutes vary widely in origin, composition, biological activity, and mechanical characteristics, encompassing allografts, xenografts, synthetic materials, and biologically enhanced constructs. This review outlines the fundamental biological principles underlying bone regeneration—including osteogenesis, osteoinduction, and osteoconduction—and addresses additional key factors such as biocompatibility, biodegradability, and mechanical strength. Current bone graft materials are classified by biological origin and functional characteristics, with an emphasis on their use in trauma surgery. Particular attention is given to the clinical applications, indications, and limitations of allograft-based solutions (such as structural allografts and demineralized bone matrix), synthetic ceramics (including calcium phosphate and bioactive glass), and biologically enhanced options, such as recombinant growth factors and stem cell therapies. In trauma settings, graft selection must be tailored to the characteristics of the defect, mechanical demands, the biological environment, and patient-specific factors. Integration with surgical technique and fixation is crucial for optimizing outcomes. Although modern substitutes show promise, none fully replicate the complex biology of autografts. Looking ahead, emerging technologies such as 3D printing, nanotechnology, and smart biomaterials offer exciting possibilities but face translational challenges. This review aims to provide practicing orthopedic surgeons with a concise, evidence-based overview of bone substitute options and their roles in trauma care. By applying core biological principles and clinical judgment, surgeons can better navigate the expanding array of graft materials to improve outcomes for patients with complex skeletal defects.