Mediastinitis is an infection of the structures in the thorax excluding the lungs and pleural space. Most cases of mediastinitis are secondary to spread of infection from a distant site or direct inoculation of organisms secondary to trauma or esophageal perforation due to malignancy. The last 30 years have seen a dramatic increase in the annual number of cardiac surgical procedures performed. Consequently, post-sternotomy surgical site infections have accounted for an increasing number of cases of mediastinitis. Despite significant advances in antibiotic therapy, surgical technique, and intensive care management, mediastinitis continues to have a high morbidity and mortality. This chapter will focus on three major categories of mediastinitis, including descending necrotizing infections, mediastinitis secondary to esophageal perforations, and post-sternotomy surgical site infections, and will discuss the pathogenesis, presentation, diagnosis, and management associated with each. The anatomy of the neck and mediastinum, which is crucial to understanding the pathogenesis and complications of mediastinitis, as well as unusual causes of mediastinitis will also be reviewed.