The numerous causes underlying mediastinal lesions require different diagnostic and therapeutic approaches, including conservative, minimally invasive, and surgical interventions. Solid lesions of a malignant nature, mostly located in the anterior mediastinum, are properly treated with surgical resection either with or without adjuvant schemes. In contrast, a surveillance program is usually recommended with solid benign tumors, depending on their size and related symptomatology. In the management of mediastinal collections, when a drainage intervention is required (suspicion of infection and symptomatology), a minimally invasive nonsurgical procedure or thoracic surgery is considered. The minimally invasive nonsurgical procedures that can be available are percutaneous radiology-guided imaging (abdominal ultrasound (US) or computed tomography (CT) scan), complete single-aspiration guided by endoscopic ultrasound (EUS) or endobronchial ultrasound (EBUS), and transmural drainage guided by EUS. Surgical debridement is feasible to treat collections, but as this entails considerable risk of postoperative complications, it is chosen only when other minimally invasive therapies are not possible. The published literature related to the interventional endoscopic approach to mediastinal lesions is scarce. Nevertheless, reports in this field reveal that interventional EUS may have a role in both the diagnosis of and therapeutic approach to mediastinal lesions, mainly in the management of mediastinal collections.