The mediastinum represents the central portion of the thoracic cavity. It is shared by many organs and tissues. Although primary tumors of the mediastinum are rare, any of the organs in the mediastinum can give rise to either benign or malignant tumors. The site is also often affected by metastatic diseases and inflammatory processes. Needless to say that the diagnosis of mediastinal lesions is challenging, not only for their rare occurrence, but also for the relative lack of experience many physicians, including pathologists, have with the diagnosis and clinical management of these lesions. This challenging issue becomes even more relevant when small biopsies including cytological specimens are used to establish a histological diagnosis. Luckily, a great number of mediastinal tumors do not require an initial histological diagnosis. In many cases, if a tumor is deemed to be amenable for surgical resection, surgery is the first line of therapy and the surgical specimen becomes the main diagnostic material. In the chapter on radiologic features, we learned that often the diagnosis of mediastinal masses can be suggested by characteristic imaging features with certain degree of confidence such as in teratomas, for example. However, in other cases, in the presence of common features of certain tumors in association with specific clinical information, a presumptive diagnosis can be reliably offered. A radiographic approach based on localization to a specific compartment and key imaging features can facilitate further evaluation of patients. This same approach to localization of the lesion is also useful to the pathologist evaluating biopsies of the mediastinum, since there is a good correlation between site of disease and the differential diagnosis.