Cushing's Syndrome (CS) is a rare disease due to chronic endogenous cortisol secretion. In the last years, new acquisitions enlarged the spectrum of differential diagnosis, historically divided into ACTH-dependent and ACTH-independent forms. Moreover, the increased awareness of the detrimental cortisol effects on cardiometabolic health and the risk of cardiovascular events lead to increased diagnosis of mild forms, especially in the context of adrenal incidentalomas. We provide and up-to-date narrative review of the most recent literature regarding the challenges of CS diagnosis. After the description of the diagnostic tools available, we describe the characterization of functional non-neoplastic hypercortisolism (formerly known as pseudo-Cushing state), then we report the subtyping of the different conditions of hypercortisolism: the differential diagnosis of ACTH-dependent forms and the management of adrenal hypercortisolism, with peculiar attention to the new genetic classification of adrenal CS, mild autonomous cortisol secretion and bilateral adrenal adenomas.
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