Incidental adrenal nodules are often found in diagnostic imaging, and differential diagnosis can be challenging. Patient history, biochemical tests, radiology, and nuclear medicine imaging are crucial to discriminate between benign and malignant lesions and accurately define the need for surgical treatment, avoiding unnecessary adrenalectomies. Non-contrast CT may detect intracellular fat (less than 10 HU), indicative of adenoma, but lesions with more than 10 HU fall into a “grey zone” where lesion size, washout CT, or chemical-shift MRI may be helpful for the definition of lipid-poor adenoma, pheochromocytoma, adrenocortical carcinoma or other malignant lesions. Moreover, nuclear medicine methods (such as 18F-FDG PET/CT and 11C-METO for adrenocortical carcinoma; 123I-MIBG, 124I-MIBG PET/CT and 68Ga-DOTANOC, 68Ga-DOTATOC, and 68Ga-DOTATATE PET/CT for pheochromocytoma) have the capabilities to assess important details, useful both for detection, differential diagnosis and therapy response assessment. Multidisciplinary evaluation is essential to create a more accurate diagnostic pathway for each lesion for the best patient management.