Background: Up-regulation of the phosphoinositide-3 phosphate kinase (PI3K) pathway is associated with poor prognosis in patients with renal cell carcinoma (RCC). Our data show that metastatic RCC patients treated with anti-vascular endothelial growth factor (VEGF) inhibitory therapy who have up-regulated PI3K pathway have a shorter progression free survival (PFS). A 80 patient Clinical Therapeutics Evaluation Program sponsored study of patients who received sorafenib +/- interferon alpha, AKT S473 was the single strongest predictor for clinical outcome in a panel of clinical and tissue variables. Similarly, reverse phase protein analysis of nephrectomy samples in patients who received presurgical bevacizumab showed that up-regulation of AKT was associated with a shorter PFS. We hypothesize that blockade of AKT in patients who are refractory to anti-VEGF therapy will eliminate one of the key drivers of tumor growth and proangiogenic signaling, and will result in prolongation of PFS. MK-2206 is a selective allosteric inhibitor of AKT. MK-2206 does not bind to the active site of AKT, and consequently does not compete with either ATP or peptide substrate for binding to AKT. This study will randomize patients who progressed on anti-VEGF therapy between MK-2206 and everolimus, a mammalian target of rapamycin inhibitor. Methods: This is an open-label, multi-center, randomized phase II study. To be eligible, patients have to have metastatic RCC, and should have progressed on an anti-VEGF agent. Up to two prior therapies are allowed. Patients will be randomized using a 2:1 ratio to receive either MK2206 or everolimus. The primary endpoint of the study is PFS. The anticipated median PFS is 4.9 months and 8.2 months for the everolimus and MK2206 arms, respectively. The secondary endpoints include safety, overall survival (OS), overall response rate (ORR) and time to failure (TTF). In addition, correlative studies evaluating primary tumor AKT levels, tumor virtual karyotype and pre versus post therapy cytokine and angiogenesis factor levels will be examined and correlate to outcome. As of February 1, 2011, the trial is open for accrual.