Most adrenocortical tumors are benign, unilateral, adrenocortical adenomas that are often discovered incidentally. Adrenocortical cancer is rare. Exceptionally, adrenocortical tumors can be bilateral. Although most adrenocortical tumors occur sporadically, they may also feature in congenital and/or familial disease. The identification of germline genetic defects in familial diseases associated with adrenocortical tumors helped to define the somatic alterations in sporadic disease: for example, overexpression of insulin-like growth factor 2 and alterations at the 11p15 locus (observed in Beckwith-Wiedemann syndrome) are also found in most adrenocortical cancers. Similarly, inactivating mutations of the TP53 gene, located at 17p13 (observed in Li-Fraumeni syndrome), can also be found at the somatic level in sporadic adrenocortical cancers, as can 17p13 allelic losses. Components of the cyclic AMP signaling pathway--for example, adrenocorticotropic hormone receptors and other membrane receptors, Gs proteins and protein kinase A--can be altered to various degrees in adrenocortical tumors. More recently, gene profiling and genetic studies have shown that the Wnt-beta-catenin signaling pathway is frequently activated in adrenocortical tumors. These research findings already have profound implications for clinical management of patients with adrenocortical tumors, for example in unraveling the genetic origin of the disease in some patients, and in the development of molecular markers for diagnosis and prognosis. The new findings should also help in the development of new therapeutic options.