Fibrodysplasia ossificans progressiva (FOP) is one of the rarest genetic conditions known. People who have this disorder essentially form two skeletons: a normal one during embryogenesis and a heterotopic one after birth. Although the general phenotype of the disease, including the presence of congenital malformations of the great toes, is constant among individuals, there is wide variation in the severity of the disorder. Studies to identify the cause of FOP currently are focused on a candidate gene approach. Bone morphogenetic proteins (BMPs) are bone-inducing morphogens that are involved in the developmental organization of the skeleton and are excellent candidate genes for disorders of heterotopic osteogenesis. We recently have demonstrated that overexpression of BMP 4 in cells from patients who have FOP is associated with this disorder. We are continuing to investigate the role of BMP-4 in the pathophysiology of FOP. An analysis of the genetic and cellular pathways that are activated ectopically in patients who have FOP will help elucidate how bone forms and grows and will lead to more effective treatments of orthotopic and heterotopic osteogenesis.