The cornerstone of medical therapy for patients affected by adrenocortical carcinoma (ACC) is mitotane, used either alone or in combination with chemotherapy. The EDP-M (etoposide-doxorubicin-cisplatin plus mitotane) regimen is the current first-line standard of care for patients with advanced ACC. However, this regimen has limited efficacy and for this reason it must be administered in the most efficient way possible, analyzing the benefits, possible adverse events, and radiologic treatment response within a multidisciplinary team. After progression on EDP-M, no second-line standard therapy is approved. Targeted treatments have demonstrated considerable cytotoxicity in preclinical trials but research in patients with ACC has yielded poor results. The response rates obtained with immunotherapy have also been disappointing: since ACC is frequently antigenic but not very immunogenic, the results obtained in immunotherapy trials seemed inferior to those attained in other solid tumors. Future studies are needed to evaluate promising strategies, such as radioligand therapy or the combination of chemotherapy with immunotherapy.