The pleural membrane consisting of pleural mesothelial cells and its underlying connective tissue layers play a critical role in immunological responses in both local and systemic diseases. The pleura, because of its intimate proximity to the lung, is positioned to respond to inflammatory changes in the lung parenchyma. Importantly, several systemic diseases have a predilection for expression on the pleural surface. Immunological responses in the pleura include the development of pleural permeability and pleural effusion formation as well as the development of pleural fibrosis and scarring. Under either circumstance, the normal functioning of the pleura is impaired and has multiple consequences leading to increased morbidity and even mortality for the patient. During infections in the pleural space, the pleural mesothelium responds by actively recruiting inflammatory phagocytic cells and allowing the movement of proteins from the vascular compartment into the pleural space. The release of chemokines by the pleural mesothelium allows for directed migration of phagocytic cells from the basilar surface of the pleura towards the apical surface. In malignant disease, the pleura may be the site of primary tumours such as mesothelioma and also the site for malignant metastatic deposits. Certain cancers such as cancers of the breast, ovary, lung, and stomach have a predilection for the pleural mesothelium. The process whereby malignant cells attach to the pleural mesothelium and develop autocrine mechanisms for survival in the pleural space are elucidated in this review. The pleura functions not only as a mechanical barrier, but also as an immunologically and metabolically responsive membrane that is involved in maintaining a dynamic homeostasis in the pleural space.