As shown in previous studies, the transforming growth factor beta superfamily of growth factors is involved in many aspects of skeletal development and regulation, including fracture repair and bone regeneration. Several studies have shown transforming growth factor beta messenger ribonucleicacid and protein expression in cells comprising fracture callus. In healing fractures in a chick model, differential isoform expression of the transforming growth factor betas was observed by in situ hybridization, with more prominent expression of the transforming growth factor beta 2 and transforming growth factor beta 3 isoforms. Small amounts of transforming growth factor beta 1 were present in early callus and increased in expression later during chondrogenesis and endochondral ossification. These findings resemble those reported in rat and human fracture callus. Transforming growth factor beta 4 expression was not significant in the chick fracture model. Transforming growth factor beta can function as a morphogen when injected subperiosteally, inducing cartilage and bone formation that morphologically resembles many of the events occurring in fracture callus. Exogenous transforming growth factor beta has been used in several critical size defect models of bone regeneration and fracture healing, with most of the studies showing increased bone or callus formation and increased mechanical stability. Numerous variables, including markedly different dose ranges and differing isoforms, dosing regimens, delivery methods, animal models, and various times and endpoint measures for analysis, make it difficult to comparatively assess the effects of transforming growth factor beta on bone healing. Additional study is necessary to satisfactorily determine the role of transforming growth factor beta in normal fracture healing and its potential for use in augmenting this process.