Chronic exposure of adrenocortical cells to high levels of ACTH (from ectopic or eutopic production) results in the development of adrenal nodules and finally neoplasias. Activation of ACTH receptor and PKA are considered vital for maintaining the highly differentiated cellular phenotype of adrenal cells and the subsequent activation of ERK is of low importance for cell proliferation. In addition, ACTH signals inactivate Akt, a kinase that promotes survival and proliferation. On the other hand, ACTH receptors are upregulated in adrenocortical adenomas of patients with ACTH-dependent hypercortisolemias intensifying the adrenal response to the already elevated ACTH, aggravating their disease. ACTH also upregulates the human homolog of Diminuto/Dwarf1 gene, which is associated with benign adrenocortical adenomas. Low expression of this gene correlates with apoptosis, indicating that its intensified expression may contribute to cell survival (52). The role of ACTH in adrenocortical tumors remains to be elucidated. It may depend on the state of differentiation of the particular cell or the presence of additional events that may decide the direction of the ACTH signal towards cell survival or inhibition of proliferation.