Bone grafting to augment skeletal healing has become one of the most common techniques in surgical practice. However, the morbidity and limited availability associated with autografts, and the potential for disease transmission, immunogenic response, and variable quality associated with allografts, have engendered a plethora of alternative materials. Such alternatives range from the simple, such as calcium sulfate and calcium phosphate materials, to the complex that contain allograft extracts, bone morphogenetic proteins, or other agents. Calcium sulfate has the distinction of being the alternative that is both one of the simplest as well as that which has the longest clinical history as a synthetic bone graft material--spanning more than 100 years. This article reviews the structure and function of calcium sulfate as a synthetic bone void filler and speculates on its future surgical role. It is anticipated that this foundation will also help assist in the understanding of how other bone graft alternatives may operate.