The efficacy of mitotane in providing objective tumour responses in patients with adrenocortical carcinoma (ACC), has been recently questioned. Experience with non specific chemotherapy is limited. Tumour responses have been reported with cisplatin administered as a single agent or in combination. Other reports however failed to show benefit from cytotoxic chemotherapy. The very low number of patients included in each study, mostly of them previously treated with mitotane, may account for these controversial results. The finding that multidrug resistance mediated by MDR-1/P-glycoprotein can be reverted by mitotane provides a rational basis for exploring the use of mitotane in combination with chemotherapeutic agents. In a multicenter cooperative (SWOG) phase II study, a combination of mitotane+cisplatin appeared active in advanced ACC, with 30% response rate in 37 eligible patients. These results prompted us to evaluate the activity of a combination chemotherapy of Eto-poside, Adriamycin and Cisplatin (EAP) in association with mitotane (4 g daily per os). Up to now we treated 6 patients, obtaining 3 partial responses. Recently, new drugs as suramin and gossypol have been show to have some activity in patients with surgically unresectable ACC, suggesting the need for further investigation. In conclusion, cytotoxic drugs+mitotane and new adrenocorticolytic/cytotoxic agents, should be explored as first line treatments in patients with advanced ACC. However, due to the extreme rarity of the disease, coordinated multicenter investigations should be highly encouraged.