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Inhibitors of the mammalian target of rapamycin (mTOR), such as rapamycin and CCI-779, have potential as anti-tumor agents against multiple myeloma (MM). In a murine xenograft model, CCI-779 demonstrated efficacy against in vivo growth of OPM-2 and 8226 MM cells. In this model, OPM-2 tumors (ED50=2 mg/kg) were considerably more sensitive than 8226 (ED50=20 mg/kg) tumors. CCI-779-induced anti-tumor responses were associated with significant inhibition of proliferation and angiogenesis and concomitant upregulation of apoptosis. OPM-2 cells were also significantly more sensitive to these CCI-779-mediated effects. Other tumor models have demonstrated that heightened AKT activity induces hypersensitivity to mTOR inhibitors. As OPM-2 cells express high levels of activated AKT (due to PTEN mutations) and 8226 cells contain predominantly quiescent AKT, this regulatory role for AKT may be present in MM cells as well. To further test this, we stably expressed an activated AKT allele in U266 (U266myr-AKT) MM cells. The in vivo growth of U266myr-AKT cells was considerably more sensitive than control U266 cells to the anti-tumor effects of CCI-779. The differential sensitivity induced by AKT activation was mirrored in an enhanced sensitivity to CCI-779-mediated apoptosis and inhibition of angiogenesis. Since previous studies demonstrated the ability of AKT/mTOR to regulate the expression of vascular endothelial growth factor (VEGF), we hypothesized that MM cells with heightened AKT activity may be more sensitive to the CCI-779-mediated inhibition of this critical angiogenic factor. In vitro, mTOR inhibitor, rapamycin, was markedly more effective at inhibiting VEGF secretion from U266myr-AKT than control cells. Our results demonstrate that AKT regulates the sensitivity of MM cells to the anti-tumor effects of mTOR inhibitors and that this may be mediated through the inhibition of AKT-dependent survival and growth factors.