Wegener's granulomatosis (WG) is currently categorized as one of the antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitides distinguished by its predilection to affect the upper and lower respiratory tracts and kidneys clinically and histologically by the presence of necrosis, granulomatous inflammation, and vasculitis. However, small biopsies, especially from the head and neck region, often lack all these diagnostic histologic findings. Other common histologic features of WG include microabscesses and scattered multinucleated giant cells in a highly inflammatory background. Support from distinctive clinical setting or positive cytoplasmic (C)-ANCA testing may help establish the diagnosis of WG in cases lacking all the typical pathologic findings. The histopathologic differential diagnosis of WG includes nonspecific inflammatory conditions, infections, angiocentric lymphomas, collagen vascular diseases, and other forms of angiitis and granulomatosis. The prognosis of WG has dramatically improved from the 18% 5-month survival rate before the era of immunosuppressive therapy to the current remission rate of over 75% with a regimen of cyclophosphamide and glucocorticoids. A significant rate of relapse and profound disease- and/or treatment-related morbidity still occur. The cause of WG remains unknown, but circumstantial evidences suggest the potential roles of ANCA and infection in the pathogenesis.