Natural history studies track the course of a disease over time, helping researchers understand the different ways a condition may manifest itself and progress. These studies can also provide insight into whether patient populations should be divided into subtypes for more targeted therapeutic approaches. Such data often represents a foundational understanding of a disease that can play an essential role in the design of clinical trials, helping investigators determine appropriate protocols and select endpoints for a study. In some cases, natural history studies can serve as an alternative to placebo arms of a clinical trial. Ahead of the upcoming Rare Drug Development Symposium, we spoke to Erika De Boever, deputy director of the Orphan Disease Center at the University of Pennsylvania School of Medicine, about natural history studies, the different types that exist, and why they play such a critical role in clinical trials for rare diseases.