The current standards of lung cancer staging are based on either imaging, utilizing computed axial tomography, positron emission tomography (PET), or both, vs tissue-based staging that involves image-guided FNA, mediastinoscopy, or intraoperative staging. Image-guided transthoracic, bronchoscopic, and EUS-guided FNA greatly facilitate lung cancer staging by having the potential to precisely sample lung lesions and virtually all mediastinal lymph node stations. Imaging modalities alone, including chest radiography, CT, MRI, and PET identify lesions suspicious for cancer but cannot make a tissue diagnosis. Therefore, imaged-based staging has approximately a 10 to 20% inaccuracy. We have described a tissue-based algorithm for the diagnosis and TNM staging of lung cancer that uses procedures with the least invasiveness and cost with the highest diagnostic yields.7For the anterior mediastinum, fluoroscopic, ultrasound, or CT-guided transthoracic FNA (which has a greater yield than bronchoscopy and is less invasive than mediastinoscopy) is our preferred primary technique for lymph node sampling.8 In the middle mediastinum, CT-guided transthoracic FNA is preferred for all nodal stations except subcarinal. EUS-guided FNA, which enables real-time transesophageal ultrasound-guided FNA within approximately 5 cm of the esophagus, is preferred for sampling subcarinal and posterior mediastinal lymph nodes because the yield is similar to CT-guided transthoracic FNA, with little or no risk of pneumothorax.1,3 The posterior mediastinum is also accessed by fluoroscopic-guided or CT-guided transthoracic FNA or video-assisted thoracic surgery. In summary, EUS-guided FNA is particularly suited for the posterior mediastinal staging, with enlarged lymph nodes in the subcarina, aortopulmonary window, paraesophageal area, and para-aortic area being the most suitable locations for EUS-guided FNA. Recent data9suggest that EUS-guided FNA may detect advanced mediastinal disease and avoid unnecessary surgical exploration in up to one in four patients who have no evidence of enlarged mediastinal lymph nodes on CT scan. While histologic tissue-based staging appears more accurate (95%), based on outcomes data, even early staging still predicts a relatively poor prognosis. Stage I has only a 60% 5-year survival, and stage II has only a 40% 5-year survival. Such poor outcomes suggest that either micrometastasis or havens of disease exist following resection for cure. Even though there is considerable prior negative data in regards to the utilization of adjuvant chemotherapy in NSCLC, data from recent randomized trials10–13 with demonstration of survival benefit increase the impetus to obtain more precise staging information.