Cushing's disease or pituitary-dependent hyperadrenocorticism (PDH) is common in dogs and rare in cats. PDH is caused by a pituitary tumor producing adrenocorticotropin (ACTH). Pituitary imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is required to assess the size and location of the pituitary adenoma in relation to the surgical landmarks. In a specialized veterinary institution, microsurgical transsphenoidal hypophysectomy has proven to be a safe and effective treatment for dogs (n=84) and cats (n=7) with Cushing's disease. Pituitary surgery requires a team approach and the neurosurgeon performing hypophysectomies must master a learning curve. The surgical results compared favorably with those for dogs with PDH treated medically with mitotane at the same institution. The recurrence rate after initially successful surgery increases with longer follow up-times. Pituitary function testing in 39 dogs with PDH treated with hypophysectomy revealed that, much more so than the other adenohypophyseal cell types, residual corticotropes present in the sella turcica after surgery are functional. Such normal ACTH secreting cells may maintain normocorticism whereas residual adenoma cells may lead to mild recurrence after relatively long periods of remission. Microsurgical transsphenoidal hypophysectomy is an effective treatment for canine and feline Cushing's disease.