With flat-panel detector mammography, radiography, and fluoroscopy systems, digital tomosynthesis (DT) has been recently introduced as an advanced clinical application that removes overlying structures, enhances local tissue separation, and provides depth information about structures of interest by providing high-quality tomographic images. DT images are generated from projection image data, typically using filtered back-projection or iterative reconstruction. These low-dose x-ray projection images are easily and swiftly acquired over a range of angles during a single linear or arc sweep of the x-ray tube assembly. DT is advantageous in a variety of clinical contexts, including breast, chest, head and neck, orthopedic, emergency, and abdominal imaging. Specifically, compared with conventional mammography, radiography, and fluoroscopy, as a result of reduced tissue overlap DT can improve detection of breast cancer, pulmonary nodules, sinonasal mucosal thickening, and bone fractures and delineation of complex anatomic structures such as the ostiomeatal unit, atlantoaxial joint, carpal and tarsal bones, and pancreatobiliary and gastrointestinal tracts. Compared with computed tomography, DT offers reduced radiation exposure, better in-plane resolution to improve assessment of fine bony changes, and less metallic artifact, improving postoperative evaluation of patients with metallic prostheses and osteosynthesis materials. With more flexible patient positioning, DT is also useful for functional, weight-bearing, and stress tests. To optimize patient management, a comprehensive understanding of the clinical applications and limitations of whole-body DT applications is important for improvement of diagnostic quality, workflow, and cost-effectiveness. Online supplemental material is available for this article. (©)RSNA, 2016.