Study Design. Reviews were conducted. Objectives. To review the biology of spine fusion healing, and to outline several fundamental principles required for the selection of a bone graft substitute. Summary of Background Data. More than 200,000 spine fusions are performed each year in the United States. The success of this procedure is limited by morbidity from iliac crest bone graft harvest and a nonunion rate that ranges from 10% to 40%. In recent years, there has been an increased understanding of the biology of spine fusion healing. In addition, there has been a focus on finding suitable substitutes for autogenous iliac crest bone graft to promote spine fusion. The selection of a specific bone graft substitute can be a daunting task for the surgeon. Methods. The available literature was reviewed and combined with the author's personal experience. Results. A basic understanding of the biology of healing in different types of spine fusions and, the differences between different categories of bone graft substitutes can help surgeons organize the graft selections process. Conclusions. In general, purely osteoconductive substitutes are less effective in adult posterolateral spine fusions, but may be suitable in the anterior spine when it is rigidly immobilized. Osteoinductive substitutes are more likely to be successful as extenders, enhancers, or substitutes for posterolateral spine fusion.