Transthoracic needle biopsy (TNB) has emerged over the past three decades as the invasive procedure of choice for the diagnostic evaluation of pulmonary nodules. The technique has proved extremely accurate in the diagnosis of malignancy, particularly when modern cytopathologic techniques are used in the evaluation of aspirated specimens. With the advent of cross-sectional imaging using CT and sonography, the applications of TNB have expanded to the diagnosis of mediastinal, hilar, chest wall, and pleural lesions. This article focuses on the indications for biopsy, the prebiopsy evaluation and patient care issues, types of image guidance, the technique of TNB, and the results and complications of the procedure. The relative cost effectiveness of TNB and comparison with alternative diagnostic methods are also reviewed.