This chapter focuses on mediastinitis. The mediastinum is the space in the thorax between the lungs. It houses the heart, great vessels, esophagus, trachea, thymus, and lymph nodes. The connective tissues of the mediastinum are continuous with the long fascial planes of the head and neck, one reason why mediastinitis was primarily a complication of pharyngeal infections until the advent of thoracic surgery. By virtue of its deep position within the thorax, the mediastinum is a relatively protected organ space. There are four major portals of entry into the mediastinum: (1) direct inoculation of the mediastinum following sternotomy (i.e., postoperative mediastinitis [POM]); (2) spread along the long fascial planes of the neck (i.e., descending mediastinitis); (3) rupture of mediastinal structures, such as the esophagus; and (4) contiguous spread of infection from adjacent thoracic structures.