Inhibition of the mammalian target of rapamycin (mTOR) pathway is a promising strategy for the treatment of mantle cell lymphoma (MCL). ncRNA growth arrest-specific 5 (GAS5), a 5' terminal oligopyrimidine (5'TOP) RNA regulated by the mTOR pathway, is necessary and sufficient for normal growth arrest in leukemic and untransformed human lymphocytes. We downregulated endogenous GAS5 in mantle cell lymphoma cell lines using RNA interference before treatment with several rapalogues. The effect of GAS5 downregulation was monitored by 3 independent analyses of cell viability, DNA synthesis, and colony-forming ability. Downregulation of GAS5 substantially reduced the effects of each rapalogue on cell viability, DNA synthesis, and colony-forming ability. Stimulation of expression of candidate tumor suppressor GAS5 is responsible for much of the cytotoxic and cytostatic effects of rapalogues in MCL, suggesting that improved targeting of this pathway may allow improvements in the therapy of this intractable lymphoma.