The parallel development of cross-sectional detection and characterization of thoracic lesions with advances in biopsy needle design and increased access to expert cytopathology has led to an expanded role for image-guided transthoracic needle biopsy (TNB) in the diagnostic evaluation of thoracic lesions. There is a growing list of indications for TNB, the most important of which is the evaluation of a solitary pulmonary nodule. A key preparatory step in planning TNB is conducting a preprocedural consultation with the pathologist, which maximizes the likelihood of a positive diagnostic outcome. Computed tomography (CT) has rapidly become the guidance modality of choice for performing TNB. While TNB is highly sensitive in the diagnosis of carcinoma, methods used to enhance the diagnostic yield for other neoplasms and benign conditions include coaxial needle placement for multiple samplings, selective use of core biopsy needles to obtain histologic specimens, and the performance of ancillary tests on the aspirated material. The complications of TNB are well recognized and include pneumothorax, hemorrhage, and systemic air embolism. Although the results of recent cost-analysis studies suggest a central role for TNB in the diagnosis of the indeterminate lung lesion, the availability and yield of alternative diagnostic and therapeutic techniques including positron-emission tomography scanning and video-assisted thoracoscopic surgery will determine its true utility.