The granule-associated elastase homologues neutrophil elastase (NE), proteinase 3 (PR3), and azurocidin (AZU) are involved in immune defense reactions of neutrophils and monocytes. Proteinase 3 and NE contribute to the destruction and elimination of microorganisms, cleave elastin and other proteins of connective tissues, and generate chemotactic activities by forming alpha 1-proteinase inhibitor (alpha 1-PI) complexes. Azurocidin is cytotoxic to certain microorganisms and chemotactic to monocytes. All three proteins are produced and packaged into azurophil granules in large quantities during neutrophil development. The genes encoding AZU, PR3, and NE are closely clustered in this sequence within 50 kb of genomic DNA and have the same transcriptional orientation. All three genes show the same exon-intron organization as neutrophil cathepsin G, mast cell chymase 1, and the lymphocyte serine proteases, granzymes A, B, and H. The AZU-PR3-NE gene cluster was mapped to the telomeric region on the short arm of human chromosome 19 (19p13.3), whereas cathepsin G, lymphocyte granzymes B and H, and mast cell chymase 1 are organized as a separate gene cluster on chromosome 14q11.2. Neutrophil-derived serine proteases are widely regarded as pathogenic factors in degenerative and inflammatory diseases with abnormal tissue catabolism. Autoantibodies against PR3 are an obligate feature in the pathogenesis of Wegener's granulomatosis, a systemic autoimmune vasculitis. In addition, PR3 appears to regulate growth and terminal differentiation of the myelomonocyte lineage. Future investigations will clarify whether allelic variations in the AZU-PR3-NE locus predispose patients to increased degradation of elastic fibers, as in pulmonary emphysema, and to the formation of autoantibodies against PR3 in patients with Wegener's granulomatosis.