What exactly is a “medical mystery”? Any one condition of illness could be diagnosed, misdiagnosed, a missed diagnosis, undiagnosed, or perhaps something else. The National Institutes of Health (NIH) specifically defines undiagnosed diseases as “long-standing symptoms or elusive medical conditions that have not been diagnosed despite extensive clinical evaluation.” What is now known as the Undiagnosed Disease Network (UDN) was a research study first established by the NIH in 2008 and is now funded by the National Institute of Neurological Disorders and Stroke. Its charge to convene experts, draw on state-of-the art technology to research human subjects at 14 US clinic locations, forge new knowledge about human bodies, “solve the most challenging medical mysteries,” and “help individual patients and families living with the burden of undiagnosed diseases.” Participants in UDN research must apply with supporting documentation from their clinicians and health records. Fewer than half of applicants are enrolled in a UDN protocol. Among those subjects who are evaluated by clinician-investigators, some receive a diagnosis. This theme issue considers a range of clinical and research ethics questions posed by diagnostic research and the UDN’s policies, practices, and public support.

Manuscripts submitted for peer review consideration and inclusion in this issue must follow Instructions for Authors and be submitted by 30 November 2024.