Cushing disease is most frequently caused by pituitary adenomas that secrete adrenocorticotrophic hormone. Transsphenoidal surgery is the treatment of choice in patients with these tumors because of reported remission rates of 69-93%. More challenging for neurosurgeons and endocrinologists, however, is management of the remaining patients whose Cushing disease is refractory to initial transsphenoidal surgery or recurs after initial remission. Here, we review the treatment options and latest surgical, medical, and radiosurgical advances for patients who have persistent or recurrent Cushing disease after transsphenoidal surgery.