Fibrosing lesions of the mediastinum represent a small but challenging group of lesions that range in etiology from infectious to idiopathic to neoplastic. The diagnosis of such lesions becomes more challenging in the setting of mediastinoscopic biopsies. In addition, over the years, there has been further accumulation of knowledge of the clinical aspects of these lesions that needs to be incorporated into their evaluation. Therefore, it is essential that in the general evaluation of these fibrosing processes, one not only carefully examines the histopathologic features of the lesion, that of a fibroinflammatory process with the appropriate histochemical and immunohistochemical studies, but also carefully evaluates the clinical presentation and imaging findings. Needless to say, as will be illustrated in this review, determining a definitive unequivocal diagnosis on a small mediastinoscopic biopsy may be difficult, and often one needs to provide guidance on the perspective of the histologic features present. In some cases, mainly tumoral conditions with extensive fibrosis, a conclusive diagnosis can be made; however, it is those cases in which the extensive fibrosis is the only histopathologic feature where more appropriate guidance is required. While this review will focus more on the non-neoplastic fibroinflammatory lesions of the mediastinum, within the discussion of differential diagnoses, we will discuss some neoplastic conditions that commonly show extensive fibrosing features.