Myeloma cell interface with microenvironmental components is critical to cell growth and survival and perceived as a major obstacle for effective disease treatment. Hence, molecules that facilitate cell-cell and cell-ECM interactions are particularly important. We have previously shown that re-expression of membranal microdomain organizers, tetraspanins CD81 and CD82, caused myeloma cell death. Herein we demonstrate that the anti-myeloma effect of CD81/CD82 involves a down-regulation of Akt, activation of FoxO transcription factors and a decrease in active mTOR and mTOR/rictor. We go on to show in a breast cancer cell line model that Akt dependent cells are more sensitive to the tetraspanin overexpression. Moreover, expression of a constitutively active Akt increased survival of CD81/CD82 transfected myeloma cell lines. Akt and mTOR afford attractive therapeutic targets in cancer yet, due to pathways' interactions, inhibitors of mTOR frequently activate Akt and vise versa. Our results demonstrate co-repression of both by CD81/CD82 implying that tetraspanins may serve as "switches" modulating pathways rather than blocking a single factor and constitute a promising therapeutic strategy in Akt dependent pathological conditions. The possibility that the tetraspanins affect metabolic control is broached as well.