Adrenocortical carcinoma is a rare endocrine malignancy with an estimated worldwide incidence of 0.5 - 2 per million/year. This neoplasm is characterized by a high risk of recurrence and a dismal prognosis owing to unsatisfactory overall survival. Surgery represents the cornerstone of adrenocortical carcinoma therapy, which can be associated to radiotherapy and adjuvant mitotane administration. In advanced cases, different chemotherapy regimens are used, but their relative efficacy is still unknown until the results of clinical trials under way will be published. Novel drugs have been recently developed based on the discovery of molecular pathways that trigger development and evolution of these tumors. More efficient treatments are widely expected in the future from these new targeted therapies as a hope of cure for patients affected with this aggressive malignancy.