Bone substitutes are increasingly used in orthopaedic surgery, with over two million bone grafting procedures performed annually. Autografts remain the gold standard for bone substitution, but they have limitations such as morbidity and limited availability. Allografts, derived from human bone, are osteoconductive but have concerns about infection risks and costs. Xenografts, derived from non-human sources, are cheap but have inconsistent results. Ceramic-based substitutes, such as hydroxyapatite (HA) and tricalcium phosphate (TCP), are widely used due to their effectiveness and resorbability. Biomimetic HA, which mimics natural HA, contains ions that enhance bioactivity. Injectable cements enable minimally invasive techniques. Bone morphogenetic proteins (BMPs) are the only approved bone-inducing growth factors for spine and tibial nonunion. Demineralized bone matrix and platelet-rich plasma have shown limited effectiveness. Experimental cell-based approaches, including mesenchymal stem cells, are promising for bone regeneration. Bone substitutes must be biocompatible, osteoconductive, osteoinductive, and resorbable. Current alternatives include ceramics, growth factors, and xenografts. While autografts are still preferred, alternatives like HA-TCP are effective and cost-efficient. BMPs are effective but expensive. Xenografts have limited success in orthopaedics. Calcium phosphate cements are synthetic, osteoconductive, and resorbable, suitable for non-load-bearing applications. Calcium sulfate is resorbable but can cause inflammation. Polymer-based substitutes, such as collagen and hydroxyapatite composites, offer good mechanical properties. Growth factors like DBM and PRP have shown promise but require further validation. BMPs are effective but costly and have limitations in certain applications. Emerging strategies include biomimetic materials, smart materials, and cell-based gene therapy. Cell-based approaches using MSCs are promising for bone regeneration. Despite advancements, alternatives to autografts lack the "Diamond theory" principles of osteogenic cells, vascularization, and mechanical stability. Ceramics are the safest and most effective substitutes. BMPs are EBM validated but expensive. Other alternatives require further clinical trials. The study highlights the importance of continued research to improve bone substitutes for clinical use.Bone substitutes are increasingly used in orthopaedic surgery, with over two million bone grafting procedures performed annually. Autografts remain the gold standard for bone substitution, but they have limitations such as morbidity and limited availability. Allografts, derived from human bone, are osteoconductive but have concerns about infection risks and costs. Xenografts, derived from non-human sources, are cheap but have inconsistent results. Ceramic-based substitutes, such as hydroxyapatite (HA) and tricalcium phosphate (TCP), are widely used due to their effectiveness and resorbability. Biomimetic HA, which mimics natural HA, contains ions that enhance bioactivity. Injectable cements enable minimally invasive techniques. Bone morphogenetic proteins (BMPs) are the only approved bone-inducing growth factors for spine and tibial nonunion. Demineralized bone matrix and platelet-rich plasma have shown limited effectiveness. Experimental cell-based approaches, including mesenchymal stem cells, are promising for bone regeneration. Bone substitutes must be biocompatible, osteoconductive, osteoinductive, and resorbable. Current alternatives include ceramics, growth factors, and xenografts. While autografts are still preferred, alternatives like HA-TCP are effective and cost-efficient. BMPs are effective but expensive. Xenografts have limited success in orthopaedics. Calcium phosphate cements are synthetic, osteoconductive, and resorbable, suitable for non-load-bearing applications. Calcium sulfate is resorbable but can cause inflammation. Polymer-based substitutes, such as collagen and hydroxyapatite composites, offer good mechanical properties. Growth factors like DBM and PRP have shown promise but require further validation. BMPs are effective but costly and have limitations in certain applications. Emerging strategies include biomimetic materials, smart materials, and cell-based gene therapy. Cell-based approaches using MSCs are promising for bone regeneration. Despite advancements, alternatives to autografts lack the "Diamond theory" principles of osteogenic cells, vascularization, and mechanical stability. Ceramics are the safest and most effective substitutes. BMPs are EBM validated but expensive. Other alternatives require further clinical trials. The study highlights the importance of continued research to improve bone substitutes for clinical use.