Through the widespread use of imaging techniques with great sensitivity adrenal tumors are often diagnosed as an incidental finding. Although the majority of these adrenal lesions are benign and without evidence of endocrine activity or malignancy, hormone hypersecretion needs to be ruled out by specific tests. In addition to the classical forms of overt adrenocortical hypersecretion, it has become evident over the recent years that modest adrenocortical steroid autonomy as present in normokalemic primary aldosteronism and subclinical Cushing's syndrome is also associated with a significant morbidity. However, detection and differential diagnosis of these subtle changes in adrenal steroidogenesis can pose a diagnostic challenge to the clinician and is dependent on tests with reliable sensitivity and specificity. Regulation of adrenocortical development and growth, which results in clinical symptoms if disrupted, is dependent upon the distinct spatiotemporal expression of a variety of transcription factors as well as stimulation by extra-adrenal peptide hormones. Contributions to the elucidation of growth regulation of the adrenal cortex come from rare familiar syndromes associated with adrenocortical tumors, expression studies of adrenal tumor samples, in vitro studies on adrenocortical tumor cell lines, and mouse models displaying adrenal growth defects. In this review, we will summarize the important molecular aspects of adrenal tumorigenesis and highlight some prospects for clinical applications.