Mediastinal staging is generally performed by the use of imaging techniques such as CT (Computed Tomography) and PET (Positron Emission Tomography), mini-invasive techniques, as TBNA (Transbronchial Needle Aspiration), EBUS-TBNA (Ultrasound-Guided Transbronchial Needle Aspiration), EUS-FNA (Endoscopic Ultra Sound Fine-Needle Aspiration), and/or surgical techniques as mediastinoscopy, thoracoscopy, mediastinothomy. Each of these techniques provides different sensitivity, specificity and predictive value: all these characteristics need to be well considered and adequately used to achieve the best possible outcome, best exploitation of available resources and least discomfort for the patient. Particularly, indicators which may suggest the need for further examination of mediastinum, following a negative CT and PET, will be discussed in this review; need for surgical confirmation after negative TBNA will be considered, also.