A central challenge of rare disease drug development is not having enough patients to conduct double blind randomized clinical trials. A well-accepted pathway to circumvent this challenge is the use of natural history studies. These studies can help define disease population, design better informed clinical trials, develop clinically meaningful endpoints and be used to establish historical controls. However, in the rare disease setting, these data are often lacking due to limited diagnostic tools, limited and dispersed patient populations and misdiagnosis. A panel discussion will explore methods to leverage natural history data including combining existing registries, refining registries to identify appropriate subpopulations and developing regulatory grade registries. Lastly, recent efforts by NIH and FDA on best practices to develop registries as well as the draft guidance "Rare Diseases: Common Issues in Drug Development" will be discussed.