This symposium will review various aspects of therapy development for rare (orphan) diseases. The difficulties and trade-offs in developing a comprehensive patient registry to assess natural disease progression and treatment effects will be highlighted using pemphigoid as a case example. The role and limitations of (observational) natural history studies instead of/in addition to placebo-controlled clinical trials within the framework of drug development and approval for enzyme replacement therapies will be discussed. Finally, a case study will be presented where a pharmaceutical company was able to successfully reach out to the community of tuberous sclerosis complex patients in order to help with orphan drug development.