Autoantibodies with the highest specificity for rheumatoid arthritis (RA) are the antibodies directed to citrulline-containing epitopes, so-called anti-citrullinated peptide/protein antibodies (ACPA). During the past decade it became clear that the presence of these antibodies was highly predictive of and specific for RA, and illustrating the importance of ACPA. Therefore, the presence of these antibodies is one of the new American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 criteria for RA. Apart from the presence of these antibodies, the composition of this antibody response matures during RA development. This review summarizes the current knowledge of the characteristics of ACPA in RA development.