It is widely held that determination of increased levels of serum autoantibodies can play an important role in the diagnosis and, in some cases, management of many autoimmune diseases. It is also widely held that such testing is fraught with problems relating to accuracy and detection of clinically relevant autoantibodies. Attempts to standardize autoantibody testing by making available standard reference sera, have helped to some degree to improve the testing. Nevertheless, problems still exist and may be causing the delayed diagnosis of severely debilitating and sometimes fatal autoimmune diseases. This paper discusses current practice, as well as, possible new approaches intended to make more robust, autoantibody determinations in all fields of medicine.