Increased emphasis has been placed in recent years on predictive biomarkers to foretell the onset or future course of disease. In autoimmune diseases, autoantibodies have proven to be valuable biomarkers because of their technical sensitivity, specificity, and stability during storage. Their predictive value is limited, however, by their prevalence. At present, predictive studies have utilized long-time evaluation of stable populations, families with one index case or retrospective investigations where large serum repositories are available. Our increasing knowledge of the steps leading from benign autoimmunity to frank autoimmune disease has suggested ways by which subtle genetic differences combined with assessment of the pattern of critical mediators can trace the progression of disease. The new tools of multiplex testing and information handling open opportunities to identify early signposts of disease.