Tuberous sclerosis complex (TSC), caused by loss-of-function mutations in the TSC1 or TSC2 genes, is an autosomal dominant disease characterized by benign tumor formation in multiple organs. Hyperactivation of mammalian target of rapamycin (mTOR) is the primary alteration underlying TSC tumor. Thus, rapamycin, as an mTOR specific inhibitor, has been assumed as a potential drug for the treatment of TSC. However, its application in TSC patients has been limited due to side effects. By analyzing Tsc1-or Tsc2-null mouse embryonic fibroblasts (MEFs), we found that loss of TSC1 or TSC2 led to a decreased sensitivity to MK-2206, a novel allosteric Akt inhibitor. Ectopic expression of a constitutively activated Akt (myristoylated Akt-1, myrAkt-1) sensitized Tsc2-null and Tsc1-null MEFs to MK-2206. Furthermore, MK-2206 increased the cytotoxicity of rapamycin in Tsc1-/-or Tsc2-/-MEFs. Moreover, the benefit of the combinatorial treatment was also demonstrated in a TSC xenograft mouse model. We conclude that the combination of rapamycin and MK-2206 may be utilized as a new therapeutic regimen for TSC.