The rational way to set a diagnosis and estimate a prognosis in rheumatology is to start by setting a tentative diagnosis and then follow a fixed scheme for laboratory testing, eg, by using an agreed algorithm. The use of order algorithms can be extended to post-test algorithms that will assist clinicians in approaching the right diagnosis and prognosis. New methods used in autoimmune serology do not deliver results that can be directly compared to those of older methods, and thus the new methods need to be thoroughly tested with sera from differential diagnostically relevant disease controls to set a clinically meaningful cut-off for positivity. Borderline positive results need to be treated with special care to avoid misuse. Early diagnosis is of great importance, and serological results can be very useful if used the right way. European efforts to secure rational diagnostic work-up in autoimmune rheumatic disease have led to a better dialogue between clinicians and laboratory scientists in several countries.