Precipitating antibodies to extractable nuclear antigens are important in the diagnosis of connective tissue diseases. Disease associations are defined using gel based techniques. Alternative technologies have been introduced, including passive haemagglutination, enzyme linked immunosorbent assay, and western blotting. This leader contains a review of the literature on the clinical usefulness of these assays, together with knowledge gained from personal experience. Using the example of systemic lupus erythematosus, the sensitivity, specificity, and positive predictive value of the assays for disease is discussed, as is their differences in performance. The conclusion drawn is that disease specificity is method dependent. Validation and audit of performance of the method selected by the investigation laboratory is essential.