Necrotizing lesions of upper respiratory tract have always been among the most enigmatic diseases of the head and neck region. Nowadays a great deal of nosographic confusion still remains along with numerous doubts concerning diagnostic and therapeutic strategies to be followed in dealing with many diseases often erroneously defined "midline granuloma". In fact, a large variety of diseases appear or may appear as midline destructive lesions in the upper respiratory tract. Each of these, including infections, immune and neoplastic disorders, obviously requires a different therapy. The clinician must have a very good knowledge of the problem in order to make a rational approach to diagnosis and therapy. Wegener's granulomatosis is quite different from "midline granuloma" and must be diagnosed promptly so that an appropriate therapy may be determined as soon as possible. Unlike in the case of "midline granuloma", a prompt therapy is often very effective and gives long periods of remission. In this disease, nevertheless, the etiopathogenesis of both diseases is unknown, precise protocols for diagnosis or treatment do not exist (every case must be considered separately) and prognosis is very poor. On the basis of their personal experience and of an accurate review of Literature, the Authors present a systemic and up-to-date monographic study focusing particular attention on the most recent diagnostic techniques, such as immunohistochemical techniques which utilize monoclonal antibodies, indispensable in the cases of "midline granuloma", and immunofluorescent techniques searching antibodies to cytoplasmic antigens of neutrophil granulocytes, of great value in dealing with Wegener's granulomatosis not only in establishing an initial diagnosis, but also in making prognosis and in controlling the evolution of the disease. The paper also discusses differential diagnosis of midline destructive disorders, highly important for a correct and rational initial approach in diagnosis. Every disease described in the section concerning differential diagnosis must be excluded in order to make an accurate diagnosis of "midline granuloma" in that no typical histopathologic or clinical signs of this particular, destructive disorder. Finally, the authors focus their attention on new etiopathogenetic hypotheses and their therapeutic implications. The most interesting of them are surely those that consider "midline granuloma" the manifestation of a malignant lymphoma as well as those that explain the recent success obtained in treatment of Wegener's granulomatosis using trimethoprim and sulfamethoxazole asserting a possible essential role of infections in the etiology of the disease.