We postulate that there exist two distinct lymphatic malformation disorders that affect bones and cause significant morbidity and mortality. Gorham-Stout disease (G-SD) is characterized by the progressive disappearance of trabecular and cortical bone. Generalized lymphatic anomaly (GLA) is characterized by missing areas within trabecular bone and sparing of cortical bone. It is likely that both diseases have a genetic etiology because they often affect multiple noncontiguous sites; however, neither disease is heritable. Both disorders cause focal skeletal fragility. Pleural, pericardial, and peritoneal effusions also frequently complicate these conditions. Case reports and small series suggest that radiation and medical therapies (predominantly interferon and/or bisphosphonates) can stabilize progressive disease. These studies are limited by inconsistent phenotyping, variation in length of therapy and follow-up, and publication bias. We performed a retrospective study of 102 patients who have been referred to our center (24 with G-SD and 78 with GLA). Our data suggest medical therapies may allow remineralization; however, we do not know whether all patients benefit or whether those that do have sustained improvement. Important next steps include a thorough study of natural history and responses to therapy in large patient cohorts, prospective interventional trials with clearly defined outcome measures, and discovery of the genetic cause(s). Recent technologic and analytic advances in DNA and RNA sequencing, improvements in recreating human disease-causing mutations in model organisms, and in high-throughput screening for new therapeutic agents create optimism that the scientific and medical community will soon achieve a detailed understanding of the causes of G-SD and GLA and devise improved therapies for patients.