Penetrating transmediastinal injuries (TMIs) are injuries that traverse the mediastinum. These injuries are most commonly caused by firearms and knives. The investigation and management algorithms for TMI have undergone changes in recent years due to increasing evidence that computed tomography (CT) in useful in the evaluation of hemodynamically stable TMI patients. Initial investigation of TMI patients depends on the question of hemodynamic stability. In unstable patients, imaging (if any) should be limited to bedside radiography and focused ultrasonography. In hemodynamically stable patients in whom a mediastinal trajectory of injury is suspected, the primary imaging modality after radiography should be multidetector CT. CT is invaluable in the assessment of TMI due to its capacity to depict the injury track as well as demonstrate both direct and indirect signs of organ injury. On the basis of the suspected trajectory and specific findings, radiologists can play an essential role in determining future patient management and investigations for each mediastinal organ, thereby expediting appropriate investigation and treatment and avoiding unnecessary and sometimes invasive tests or surgery. The authors provide an up-to-date and evidence-based approach for the management of hemodynamically unstable and stable patients with suspected TMI, discuss management algorithms and CT protocols, and highlight common and uncommon imaging findings and diagnostic pitfalls associated with vascular, cardiac, esophageal, tracheobronchial, pleural, and pulmonary injuries. Online supplemental material is available for this article.