Abstract: Adrenocortical carcinoma (ACC) is the most prevalent malignant tumor of the adrenal gland and is characterized by a poor prognosis in its advanced stages. Surgical resection of the tumors is typically limited to patients diagnosed in the clinical stages Ⅰ and Ⅱ, leading to a high postoperative recurrence rate. The combination of mitotane (M) with etoposide (E), doxorubicin (D), and cisplatin (P) (EDP-M) is currently the only approved first-line treatment regimen for advanced ACC. However, the efficacy of chemotherapy and radiation therapy in ACC remains limited. If the EDP-M regimen proves ineffective, there are no standardized or universally accepted second-line systemic treatment alternatives. Research advancements in the molecular mechanisms of ACC in recent years has led to increasing investigations on tyrosine kinase inhibitors (TKIs) targeting EGFR, VEGFR, and mTOR, as well as immune checkpoint inhibitors (ICIs). Moreover, previous studies have identified mutations in CTNBB1, TP53, KDM5A, CENP-H, and other genes that may serve as therapeutic targets or biomarkers, thereby expanding the treatment options available for ACC. ICIs are effective against diverse cancer types, including non-small cell lung cancer (NSCLC), liver cancer, renal cell cancer, and urothelial cancer. Ongoing exploration into targeted therapies and immunotherapy, especially combination treatments, holds the promise of extending the survival of patients and enhancing their quality of life.