How do complex healthcare systems that are organised into distinct speciality areas achieve effective patient care transitions when patients present with a rare constellation of symptoms that affect multiple body systems? How do these patients challenge existing ways of organising tasks, clinical activities, and interdependent responsibilities? The current study applies a sociotechnical systems perspective to understand how these complex work design and care-related challenges were resolved by the Western Australian Undiagnosed Diseases Program. We conducted a two-year longitudinal, qualitative study of this program, conceived to improve the diagnosis and management of patients with rare, multi-system disorders by piloting a re-design of the local system of diagnostic work. Specifically, we (1) compared the configuration and effectiveness of the old system and the re-designed system; and (2) analysed the process of system re-design (i.e., the design, implementation, and operation of the program) in order to understand the factors that contributed to – or inhibited – its success. We discuss the theoretical and practical implications of our findings for effectively re-designing complex, trans-organisational work systems.