Cross-sectional imaging of the chest with computed tomography (CT), magnetic resonance imaging, and at times, ultrasonography exquisitely delineates mediastinal, hilar, and pleural pathologies. The treatment of patients with these pathologies is often based on the results of image-guided biopsies. CT and ultrasonography have been used successfully for targeting and sampling mediastinal, hilar, and pleural masses, with high sensitivity and near-perfect specificity. These procedures are performed by interventional radiologists in an outpatient setting with local anesthesia and conscious sedation. Major complications are rare, and the minor complications seen are easily managed. Minimally invasive, image-guided biopsy often obviates the need for more invasive procedures such as thoracoscopy or mediastinoscopy.