ACTH-independent, cortisol-producing hyperplasia is caused by 2 distinct disorders, primary pigmented nodular adrenocortical disease (PPNAD) and ACTH-independent macronodular adrenal hyperplasia (AIMAH). We will review recent findings on the clinical and molecular aspects of PPNAD and AIMAH. Inactivating mutations of PRKAR1A on 17q22-24, which codes for the type 1A regulatory subunit of protein kinase A, have been found in a subgroup of patients with PPNAD with and without Carney complex. AIMAH is a rare condition in which cortisol secretion may be mediated by non-ACTH circulating hormones such as gastric inhibiting polypeptide (leading to food-dependent Cushing's syndrome), vasopressin, catecholamines, luteinizing hormone, serotonin, angiotensin-II or leptin. The primary etiology of AIMAH remains unclear. Recently, we studied the expression profile of AIMAH by genomic cDNA microarray analysis. Several candidate genes were identified, suggesting pathways that affect the cell cycle, adhesion and transcription as possible mediators of adrenocortical hyperplasia.