Mediastinal lymphadenopathy can be a manifestation of either pulmonary or extrapulmonary conditions. This chapter provides clinical insights that help discriminate the various conditions associated with mediastinal lymphadenopathy. It compares the utility of various imaging modalities in detecting and defining the enlarged lymph nodes and elaborates on the lymph node characteristics that distinguish between the various competing differential diagnoses. It also describes the modern IASLC classification system and discusses the rational choice of interventional modalities for the histopathological sampling of specific mediastinal lymph node stations.