Abstract: Since the first report of a “subclinical” Cushing’s syndrome dated back to the early 1970s [1], a great deal of effort has been put to understand the molecular pathogenesis and the clinical correlates of this condition. Despite the exponential number of publications over the last years, it is still difficult to draw definitive conclusions on the clinical impact of incidentally diagnosed hypercortisolism, not associated with a clear Cushing’s phenotype. As every physician involved in the management of adrenal diseases knows, the main source of uncertainty resides in the definition of this pathological condition, which generates difficulties in achieving comparable results among different studies, and the lack of well-designed prospective studies covering a long time span, leading to difficulties in estimating the prevalence of cortisol-associated comorbidities and longterm consequences. However, keeping in mind those limitations, evidence from long-term retrospective studies has indirectly shown that a mild, but sustained, cortisol hypersecretion can be related to an increased risk of cardiovascular and metabolic correlates, which seems to be related to the cortisol secretion, as well as to the progressive secreting pattern over time [2–4]. Most of the studies on long-term consequences are focused on unilateral adrenocortical tumors, which represent the most frequent entity in radiological series. Lately, an increasing number of studies have been focused on the analysis of hormonal and clinical characteristics of bilateral incidentalomas, raising attention to the difficulties of the clinical management of those tumors. The recent advances in the biology of cortisol-secreting tumors have also shed light on the molecular events underlying bilateral adrenocortical tumors, which can be very different from their unilateral counterpart and involve novel pathogenic pathways and previously unknown regulatory mechanisms. The discovery of mutations in the ARMC5 gene in a substantial number of patients with bilateral adrenal hyperplasia and hypercortisolism [5] has broadened the view on the molecular mechanisms underlying adrenocortical hyperplasia, adding an important piece of knowledge to our understanding of tumorigenesis and hormonal hypersecretion in adrenal tumors. Research on aberrant receptors and paracrine regulation of cortisol secretion has provided evidence that the pathophysiology of bilateral masses can be extremely complex. According to the results of in vivo and in vitro studies, the presence of illegitimate receptors is indeed a frequent event among patients with bilateral adrenocortical hyperplasia, with a prevalence that rises up to 87 % [6]. Moreover, after the first pioneering studies [7], the discovery of intra-adrenal adrenocorticotropic hormone (ACTH) production in a substantial number of patients with hypercortisolism [8] has completely changed the knowledge on the feedback mechanisms involved in adrenal steroidogenesis. The review published by Paschou and colleagues [9] was aimed to investigate the relationship between morphological characteristics of the adrenal glands and the secretory pattern, with focus on incidentally discovered adrenocortical tumors and subclinical hypercortisolism. Based on the data provided by six studies published between 2011 and 2015, the main finding of the review is that the overall prevalence of subclinical hypercortisolism is increased in bilateral adrenal incidentalomas vs. unilateral adenomas. Surprisingly, the * Guido Di Dalmazi Guido.Di_Dalmazi@med.uni-muenchen.de gdd1982@gmail.com