Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis frequently presents with renal involvement manifested by a focal segmental necrotizing glomerulonephritis, which is typically pauci-immune. Although considerable insight has been gained regarding potential mechanisms of organ damage, researchers have remained relatively ignorant of the initiating factors breaking immune tolerance. A recent report has provided evidence that molecular mimicry may be critical, with immune responsiveness toward a bacterial fimbrial protein inducing a cross-reactive autoimmune response toward lysosomal-associated membrane protein-2 (LAMP-2). Use of an experimental model demonstrates that this response generates ANCA and provokes pulmonary-renal disease, reminiscent of human ANCA-associated vasculitis. Greater understanding of the immune mechanisms underlying the development of ANCA should lead to more focused approaches to the treatment of small-vessel vasculitis.