Bone regeneration is a complex physiological process essential for normal fracture healing and continuous skeletal remodeling. It involves the formation of new bone tissue and is crucial in conditions requiring large-scale bone regeneration, such as skeletal reconstruction after trauma, infection, or tumor resection. Current strategies include autologous bone grafts, allografts, growth factors, and osteoconductive scaffolds. Recent advancements focus on tissue engineering, gene therapy, and systemic enhancement to improve bone repair. However, limitations such as limited availability of autologous bone, high costs, and potential complications persist. Bone regeneration techniques include distraction osteogenesis, the Masquelet technique, and biophysical stimulation methods like low-intensity pulsed ultrasound. Bone grafting, particularly with autologous bone, remains the gold standard due to its osteoinductive, osteogenic, and osteoconductive properties. Allogeneic bone grafts are alternatives but have reduced osteoinductive properties and potential immunogenicity. Bone-graft substitutes, such as synthetic scaffolds, offer alternatives but require further development to match natural bone properties. Mesenchymal stem cells (MSCs) are critical for bone regeneration, but their availability and quality vary. Techniques like bone marrow aspiration concentrate (BMAC) and in vitro expansion aim to enhance MSC availability. However, these methods face challenges such as cost, contamination risks, and limited cell proliferation. Alternative sources of MSCs, including peripheral blood and adipose tissue, are being explored but show variable efficacy. Scaffolds and bone substitutes play a key role in bone regeneration, providing structural support and promoting cell migration and differentiation. Advances in scaffold design, including biodegradable and bioactive materials, aim to improve mechanical properties and integration with host tissue. Tissue engineering combines cells, scaffolds, and growth factors to regenerate functional bone tissue, offering promising alternatives to traditional methods. Gene therapy and systemic agents like growth hormone (GH) and parathyroid hormone (PTH) are being investigated to enhance bone regeneration. These approaches aim to stimulate bone formation and improve bone healing. However, safety concerns and long-term effects need further study. The mechanical environment is also crucial for bone regeneration, influencing cell behavior and tissue integration. Overall, while significant progress has been made in bone regeneration, challenges remain in optimizing local and systemic strategies to achieve effective and sustainable bone repair. Future research aims to develop novel therapies that address these limitations and improve outcomes for patients with complex bone defects.Bone regeneration is a complex physiological process essential for normal fracture healing and continuous skeletal remodeling. It involves the formation of new bone tissue and is crucial in conditions requiring large-scale bone regeneration, such as skeletal reconstruction after trauma, infection, or tumor resection. Current strategies include autologous bone grafts, allografts, growth factors, and osteoconductive scaffolds. Recent advancements focus on tissue engineering, gene therapy, and systemic enhancement to improve bone repair. However, limitations such as limited availability of autologous bone, high costs, and potential complications persist. Bone regeneration techniques include distraction osteogenesis, the Masquelet technique, and biophysical stimulation methods like low-intensity pulsed ultrasound. Bone grafting, particularly with autologous bone, remains the gold standard due to its osteoinductive, osteogenic, and osteoconductive properties. Allogeneic bone grafts are alternatives but have reduced osteoinductive properties and potential immunogenicity. Bone-graft substitutes, such as synthetic scaffolds, offer alternatives but require further development to match natural bone properties. Mesenchymal stem cells (MSCs) are critical for bone regeneration, but their availability and quality vary. Techniques like bone marrow aspiration concentrate (BMAC) and in vitro expansion aim to enhance MSC availability. However, these methods face challenges such as cost, contamination risks, and limited cell proliferation. Alternative sources of MSCs, including peripheral blood and adipose tissue, are being explored but show variable efficacy. Scaffolds and bone substitutes play a key role in bone regeneration, providing structural support and promoting cell migration and differentiation. Advances in scaffold design, including biodegradable and bioactive materials, aim to improve mechanical properties and integration with host tissue. Tissue engineering combines cells, scaffolds, and growth factors to regenerate functional bone tissue, offering promising alternatives to traditional methods. Gene therapy and systemic agents like growth hormone (GH) and parathyroid hormone (PTH) are being investigated to enhance bone regeneration. These approaches aim to stimulate bone formation and improve bone healing. However, safety concerns and long-term effects need further study. The mechanical environment is also crucial for bone regeneration, influencing cell behavior and tissue integration. Overall, while significant progress has been made in bone regeneration, challenges remain in optimizing local and systemic strategies to achieve effective and sustainable bone repair. Future research aims to develop novel therapies that address these limitations and improve outcomes for patients with complex bone defects.