Some of the most significant advances in biomaterials over the last 20 years have been in the field of bone graft substitutes. Additionally, bone growth proteins were one of the first tissue-specific morphogenic factors to be characterized and produced by recombinant genetic technology. Consequently, the development of a new generation of totally synthetic, biologically active bone graft substitutes is just now beginning to move from the laboratory to clinical testing. It is entirely possible that within the next 10 to 15 years, the majority of "bone grafting" in craniofacial reconstructive surgery and in orthopedic surgery may be done with biologically active synthetic bone graft substitutes rather than natural bone sources. In fact, the harvesting of autogenous grafts may eventually prove to be the exception rather than the standard of care. Regardless of whether the potential of biologically active bone graft substitutes is ever fully realized, we now have a large number of synthetic alternatives to autogenous bone grafts for craniofacial skeletal augmentation and reconstruction. The reality of these synthetic bone graft substitutes is that no single material is "the best" for all applications. Instead, the specific biomaterial must be tailored to the individual site of application to achieve optimal results. The synthetic bone graft substitutes reviewed in this article represent only the "core" of synthetic biomaterials from which synthetic bone graft substitutes can be selected. Other articles in this monograph highlight the roles that various natural and biologically active bone graft substitutes play in craniofacial skeletal augmentation and reconstruction.