Transthoracic needle biopsy (TNB) of the mediastinum is an accurate, safe, and cost-effective diagnostic tool for the evaluation of mediastinal masses and lymphadenopathy. The technique is most useful in the staging of carcinoma, where it serves as a less expensive and minimally invasive alternative to mediastinoscopy for establishing unresectability. With recent advances in immunohistochemical and core-biopsy techniques, TNB has become more accurate for establishing the initial diagnosis of lymphoma and for confirming recurrent disease. Core-needle biopsy has improved the accuracy of TNB and is particularly useful when fine-needle aspiration fails to yield a specific diagnosis, or when lymphoma or a noncarcinomatous lesion is suspected.