The prognosis of advanced adrenocortical carcinoma (ACC) is dismal but heterogeneous. In 2011, mitotane is the only drug approved in Europe and US for the treatment of advanced ACC. Mitotane exerts both antisecretory and antiproliferative effects, which are delayed over time, and requires careful biological and morphological evaluations coupled with mitotane plasma measurement monitoring. In the absence of demonstration of any superior activity of combined polychemotherapy, the least toxic regimen should be considered in routine care. Locoregional therapies, including surgery of the primary tumor and metastases, should be considered part of the therapeutic arsenal. A prolonged survival can be observed in the case of tumor objective response and/or high plasma mitotane levels. New protocols are urgently needed, coupled with ancillary studies dedicated to progress in the findings of predictors or surrogates. International networks and comprehensive databases gathering clinical and biological data constitute the prerequisites for progress.