It has recently been discovered that anti-citrullinated protein antibodies (ACPA) are present in 50% of patients with early rheumatoid arthritis (RA). Assays for detecting ACPA have been shown to have very good diagnostic and predictive characteristics, and they may facilitate the identification of patients with early arthritis who need aggressive treatment. In addition to their diagnostic and predictive properties, ACPA have also provided new insights into the pathophysiology of RA. The specific association of certain genetic and environmental risk factors with ACPA-positive but not with ACPA-negative RA, has led to new concepts of the underlying pathogenetic mechanisms. The fact that ACPA-positive patients have a more severe disease course with greater joint destruction has also fueled the hypothesis that ACPA themselves may be pathogenic. Although there is no direct proof for this intriguing theory so far, it is clear that ACPA allow the classification of RA patients into two different disease subsets that are associated with distinct pathophysiological mechanisms and clinical outcomes. Rheumatoid arthritis (RA) is a chronic, potentially destructive, arthritis which has a large impact on patients' quality of life(1). It has become clear that in order to be able to prevent disease progression and joint destruction, RA needs to be diagnosed early, which requires diagnostic markers which can reliably predict disease development and progression(2). Some of the most attractive diagnostic markers are autoantibodies. Rheumatoid factor (RF) has long been known to be a marker of future RA development(3), but more recently, a better diagnostic and predictive marker has emerged in the form of anti-citrullinated protein antibodies (ACPA).