To characterize the status of the mammalian target of rapamycin pathway using formalin-fixed, paraffin-embedded specimens from patients with primary and metastatic pheochromocytoma. Tissue microarrays were built from 19 normal adrenal medullas, 39 primary pheochromocytomas, and 8 unrelated metastatic pheochromocytomas. In 2 of the 8 cases of metastatic pheochromocytoma tissues, samples from the primary tumor were available. The expression levels of phosphatase and tensin homolog, phosphorylated Akt, phosphorylated S6, p27, and c-myc were evaluated by immunohistochemistry. The levels of phosphatase and tensin homolog and p27 were greater in the nontumor tissue than in the primary and metastatic pheochromocytomas. Increasing levels of phosphorylated Akt were noted in the nontumor adrenal medulla, primary pheochromocytomas, and metastatic pheochromocytomas. Finally, the levels of phosphorylated S6 were greater in the metastatic pheochromocytomas than in the nontumor adrenal medulla and primary pheochromocytomas. We found evidence of dysregulation of the mammalian target of rapamycin pathway in primary and metastatic pheochromocytomas, with increased phosphorylated S6 and phosphorylated Akt, and decreased phosphatase and tensin homolog and p27 expression levels. Because the currently available treatment modalities are less than optimal, our findings lend additional support to continuing to explore the utility of mammalian target of rapamycin pathway-targeted therapy for pheochromocytomas. © 2012 Elsevier Inc. All Rights Reserved.