Major changes have recently occurred in the clinical presentation, diagnosis, and management of primary lesions of the mediastinum. New diagnostic techniques and improved therapy have led to more objective preoperative diagnoses as well as better long-term results. These features are clearly demonstrated in a series of 400 consecutive patients with primary lesions of the mediastinum seen at Duke University Medical Center. Of these, 99 (25%) had a primary cystic lesion. The primary tumors included thymic neoplasms (17%), neurogenic tumors (14%), lymphoma (16%), germ cell tumors (11%), and a miscellaneous group. Malignant neoplasms were present in 166 patients (42%). The anterosuperior mediastinum was the most commonly involved site of a primary cyst or neoplasm (54%), followed by the posterior mediastinum (26%) and the middle mediastinum (20%). Symptoms were present in 62% of the patients and included chest pain (30%), dyspnea (16%), fever and chills (20%), and cough (16%). Of the lesions found on routine chest roentgenograms, 83% were benign. In contrast, 57% of the lesions in symptomatic patients were malignant. Prior to 1967, 94% of asymptomatic lesions were benign, but this figure has now decreased to 76%. Fifty percent of symptomatic patients had a malignant neoplasm before 1967 compared with 62% after that year. Newer diagnostic techniques have greatly enhanced the accuracy of the preoperative diagnosis. They include radioisotopic scanning, monoclonal antibodies, hormonal assay, electron microscopy, fine-needle aspiration biopsy, computed tomographic scans, and magnetic resonance imaging. Each has a definite role and is specifically illustrated as being quite important in this series.(ABSTRACT TRUNCATED AT 250 WORDS)