The heterogeneity of the adrenocortical carcinoma (ACC), pheochromocytoma and paraganglioma cell phenotypes requires different experimental preclinical models to reproduce the peculiarity of these adrenal malignancies. Different models have been generated, either in vitro or in vivo, as cell lines growing in both two-dimensional or in three-dimensional settings; however, in particular for pheochromocytoma/paraganglioma (PPGL), new cell models are urgently needed. As in in vivo models, ACC cells or tumor tissue xenografts have been subcutaneously administered to immunocompromised mice for localized propagation and tumor growth. For ACC and PPGL, multiple transgenic mouse models are now available, obtained by genetic modifications which may recapitulate the heterogeneity of human disease. Interestingly, given the physiological relevance of the functional interaction occurring between the steroidogenic-cortical and the chromaffin-medullary components of the adrenal gland, it is likely that the adrenal/medulla crosstalk may also affect the pathogenesis and progression of adrenal tumors. The peculiar organization of mammalian adrenals with a portal system connecting cortex and medulla strongly supports the evolutionary importance of the crosstalk inside the same gland.