The recent demonstration of efficacy in the treatment of rheumatoid arthritis with B-cell-depleting therapy, along with the increasing understanding of the role of anticitrullinated protein antibodies (ACPA) have begun to provide new insights into the pathogenesis of this complex disease. This manuscript reviews the current understanding of ACPA with regard to clinical associations and pathogenic mechanisms in preclinical animal models. These data are synthesized into a model of the development of rheumatoid arthritis that refocuses attention on the role of B cells and immune complexes, returning in part to the origins of scientific investigation in this disease, and points to directions of research that are necessary to achieve the full therapeutic, diagnostic, and prognostic potential of the ACPA antigen-antibody system.