Adrenocortical carcinoma (ACC) and pheochromocytoma (PHEO) are the two most prevalent primary malignancies in the adrenal gland. ACC diagnosis relies on multiparametric scoring systems or diagnostic algorithms that are endorsed by the WHO classification. These systems incorporate multiple histopathological features, with or without ancillary investigations, but none of them is unequivocally superior to the others. PHEO is a non-epithelial neuroendocrine neoplasm and, in line with a general concept for neuroendocrine neoplasms in other organs, it is biologically malignant by definition. However, histopathology is a key element in predicting clinical malignancy, although the scoring systems proposed to date are not as well established as for adrenocortical tumors, and therefore have low impact and insufficient reliability to be accepted by the WHO as mandatory in the diagnostic workup. Immunohistochemistry is an essential complement of the pathology workup for both entities, as it helps to define the adrenocortical or medullary origin of the lesions and adds information of prognostic relevance. Moreover, both in ACC and PHEO, immunohistochemistry is a very useful approach to screen for the presence of familial predisposition, considering the high prevalence of hereditary forms in these tumor entities.