Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex, associated with a generally dismal prognosis owing to its aggressive behavior. The clinical management of ACC is complicated by the inadequacy of current diagnostic modalities to accurately distinguish benign from malignant adrenocortical tumors. In addition, efforts to better predict clinical tumor behavior are limited by the lack of a better understanding of the molecular mechanisms of adrenocortical carcinogenesis. There have been no significant improvements in the treatment of ACC. Thus, there is a pressing need for the development of new therapeutic approaches for patients with ACC, as most patients present with advanced locoregional and metastatic disease. The prospects of identifying diagnostic and prognostic markers or gene profiles for ACC have significantly improved with the development of genome-wide gene-expression analysis. Since 2003, several studies have reported distinct gene-expression profiles between benign and malignant adrenocortical tumors that may have diagnostic and prognostic clinical utility. In this article, we discuss the limitations of the clinical management of ACC, and the gene-expression profile studies that have attempted to address these limitations.