Pulmonary nodules that are surrounded by aerated lung cannot be visualized with sonography. Therefore, percutaneous biopsy must be guided with computed tomography or fluoroscopy. Although this restriction only applies to central lung nodules, it has permeated referral patterns for other thoracic lesions and has retarded the growth of ultrasound-guided interventions. Nevertheless, sonography is an extremely flexible modality that can expeditiously guide many biopsy procedures in the thorax. Peripheral pulmonary nodules can be successfully biopsied with success rates exceeding 90% and complications rates of less than 5%. Orienting the probe parallel to the intercostal space facilitates biopsies of peripheral pulmonary nodules. Anterior mediastinal masses that extend to the parasternal region are often easily approachable provided the internal mammary vessels, costal cartilage, and deep great vessels are identified and avoided. Superior mediastinal masses can be sampled from a suprasternal or supraclavicular approach. Phased array probes or tightly curved arrays may provide improved access for biopsies in this location. Posterior mediastinal masses are more difficult to biopsy with ultrasound guidance because of the overlying paraspinal muscles. However, when posterior mediastinal masses extend into the posterior medial pleural region, they can be biopsied with ultrasound guidance. Because many lung cancers metastasize to the supraclavicular nodes, it is important to evaluate the supraclavicular region when determining the best approach to obtain a tissue diagnosis. When abnormal supraclavicular nodes are present, they often are the easiest and safest lesions to biopsy.