Aspects of pathogenesis of primary systemic vasculitis are highlighted in this review. The cause of these entities is still obscure, although new information on the possible role of infections has emerged. Success of antimicrobial treatment to ameliorate systemic vasculitis, for which proof was recently provided, adds to the new information. Apart from new data that point to a precipitating role for environmental toxins the background for development of these diseases is most likely genetic predisposition. Reports on hereditary alpha 1-antitrypsin deficiency, the link between systemic vasculitis and human leukocyte antigen molecules, and an animal model of spontaneous granulomatous arteritis in mice with a hereditary deficit in Fas-mediated apoptosis, are some of the new data that strongly favor genetic predisposition. Progress has been made in the process of identification of the agonists and antagonists in the front line of vasculitic inflammation. The interaction of blood cells (e.g., neutrophils and monocytes) with vascular endothelium has become more evident as have the signals for the release of harmful proteolytic enzymes. Antineutrophil cytoplasmic antibodies, which are important markers of disease, may be actively involved in these processes.