Discerning malignancy in resected adrenocortical neoplasms can pose diagnostic difficulty. Macroscopic examination is the first important step toward diagnosis and should include accurate measurement of weight and dimension of the specimens and description of the cut surface of the tumors. It is also important to sample the specimens for histological diagnosis near foci of hemorrhage and/or necrosis. Histological scoring systems evaluating multiple parameters, especially the criteria of Weiss, have been shown to be reliable in differential diagnosis between adrenocortical adenoma and carcinoma. A tumor is defined as adrenocortical carcinoma when three or more of the following criteria are met; (1) high nuclear grade, (2) mitotic rate six or more per 50 high power fields, (3) atypical mitosis, (4) clear cells less than 25%, (5) a diffuse architecture pattern in more than one-third of the tumor, (6) confluent necrosis, (7) venous invasion, (8) sinusoidal invasion, and (9) capsular invasion. The criteria are relatively straightforward and considered the most effective standard for diagnosis of adrenocortical malignancy. However, great care should be taken in applying the criteria to histological evaluation of two relatively rare and peculiar adrenocortical tumors, adrenocortical oncocytoma and pediatric adrenocortical neoplasms. At this juncture, ancillary biological or molecular markers are of little practical value in terms of differential diagnosis between adrenocortical adenoma and carcinoma but tumors with MIB1 or Ki-67 labeling index more than 2.5 may be considered malignant. Prognostic markers of adrenocortical carcinoma have not been established other than complete respectability of the tumor. There are also no surrogate markers for predicting response to therapy with Mitotane, an adrenolytic agent. It sometimes is important for surgical pathologists to differentiate adrenocortical carcinoma from metastatic malignancies of other sites. An immunohistochemical evaluation of adrenal 4 binding protein (Ad4BP) or SF-1, a transcription factor of all steroidogenesis, can aid in this differential diagnosis because nuclear immunoreactivity for this transcription factor is relatively specific to steroid producing cells.