Systemic Lupus Erythematosus (SLE), also known as lupus, is an autoimmune disorder which is difficult to diagnose due to its manifold symptoms. Its complexity is part and parcel of the epistemological changes that scientific biomedicine is undergoing which in turn influence clinical practice. These changes lead to the well known and often-discussed frustration of patients who suffer from elusive disorders, long-term or chronic illnesses, and medically unexplained symptoms. Using ethnographic observations in combination with grounded theory methods this study explores SLE as one example of complex syndromes that the clinical practice of late modernity seems to bring about. It concentrates on the difficulties of diagnosing complex disorders from a medical point of view, then goes on to describe the impact this has on patients’ lives, and their reaction to this situation. I argue that ambivalent diagnosis leads to existential uncertainty amongst patients which in turn influence the doctor–patient relationship. In concluding, I suggest that medical sociology has to move from merely describing and analysing this emerging situation to suggesting strategies for integrating experiential knowledge into clinical practice, especially when it comes to medical and personal management of chronic disorders such as SLE.