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The management of adrenocorticotropic hormone (ACTH)-dependent Cushing's disease implies difficulties in the differential diagnosis, in the detection of minute pituitary adenomas, as well as in the radical removal of invasive adenomas. Magnetic resonance imaging (MRI) is unspecific and often negative in minute adenomas of three or less millimeters diameter. The trias of detectable ACTH, suppression of cortisol in the high-dose dexamethasone test, and stimulation in the corticotropin-releasing-hormone (CRH)-test has a high accuracy to prove pituitary dependency. In unclear cases, the use of inferior petrosal sinus sampling (IPSS) or cavernous sinus sampling (CSS) for the exclusion of ectopic ACTH-syndrome is currently advised especially in cases where cranial MRI is negative. The reliability of these methods to localize the mostly lateralized microadenomas is still discussed. Transsphenoidal microsurgical adenomectomy, the accepted primary therapy of Cushing's disease, has been published from experienced pituitary centers with remission rates ranging from 70% to 98% in the last decade. False diagnosis (pseudo-Cushing, ectopic ACTH-syndrome), incorrect adenoma localization by IPSS or CSS, and the rate of minute or non-resectable invasive tumors influence the results. The handling of minute specimen implies problems for surgeon and pathologist. Intraoperative tumor localization was improved by ACTH measurement from the cavernous sinus and the adenoma itself, by cytology, and frozen sections. The histology of the anterior lobe (rate of Crooke's cells) bears information of clinical relevance. Invasive macroadenomas may deserve repeat microsurgery, medical treatment, and radiosurgery.