Adrenocortical carcinoma (ACC) is a rare but highly malignant tumor. Despite some progress in diagnostic and therapeutic approaches, the overall survival rate of patients with ACC remains poor. Surgery is the treatment of choice for patients with resectable tumors and for recurrent disease. However, most ACCs in adults are diagnosed with advanced disease, limiting therapeutic options. Thus, reliable clinical and molecular markers for the diagnosis of early stages of ACC and effective alternative therapies are needed. A prerequisite for the development of new diagnostic tools and therapeutic options in the management of patients with ACC is the elucidation of the molecular pathogenesis of adrenal tumorigenesis. Our understanding of molecular pathways involved in adrenocortical growth and differentiation has increased substantially over the last decades. Contributions to the elucidation of some aspects of the disruption of growth regulation of the adrenal cortex come from rare familiar syndromes associated with ACC, mouse models of adrenal tumor growth, and in vitro studies on adrenocortical tumor cell lines. In this review, we summarize the important molecular aspects of adrenal tumorigenesis and highlight some prospects for future clinical applications.