Anti-neutrophil cytoplasmic autoantibodies (ANCA) with specificity for myeloperoxidase (MPO) or proteinase 3 (Pr3) are associated with systemic small-vessel vasculitides (SVV). Detection of ANCA is an established clinical tool in disease diagnosis and monitoring. Based on clinical and in vitro experimental evidence, a pathogenic role for ANCA has long been suspected, however, in vivo models in which causality can be tested have been lacking. Recently, an exciting novel rat model of MPO-ANCA-associated vasculitis has been described, which provides compelling evidence that MPO-ANCA are a primary pathogenic factor in SVV by augmenting leukocyte-endothelial interactions and vascular wall damage.