Fibrous dysplasia (FD) is caused by somatic mutations in GNAS and activation of the cAMP-regulating protein, Gs alpha ( gsp ). gsp inhibits differentiation of stem cells to mature osteogenic cells, resulting in replacement of normal bone with a highly proliferative stroma composed of cells that express osteogenic markers. Apoptosis follows, leaving affected regions with bone that may no longer harbor significant numbers of mutated cells, but is deformed and mechanically unsound. Key features of FD that relate to the pathophysiology are overexpression of the bone remodeling proteins RANK/RANKL and the mineral metabolism-regulating hormone, FGF23. Extraskeletal manifestations include a number of hyperfunctioning endocrinopathies, which can worsen FD. The mainstay of treatment for FD is surgical. Outcomes have improved due to a better understanding of the natural history of FD, improvement in surgical techniques and devices, and recognition that curettage with bone grafting is often futile. Bisphosphonates effectively relieve bone pain and there are promising preliminary data that the anti-RANKL drug denosumab may be beneficial. An effort is underway at the NIH to identify molecules that target gsp , with the goal to develop drugs to treat FD and associated endocrinopathies. Hope for further progress resides in continued support of ongoing research, establishment of an international network of investigators/centers of excellence, and compilation and sharing of high-quality data – best accomplished through integrated and collaborative efforts involving government agencies, academic centers, cohesive patient-based support groups, and industry.