Abstract We have previously demonstrated that the hematopoietic cell specific Rho GTPase Rac2 plays not only an essential role in regulating multiple actin-based functions of bone marrow derived mast cells, such as adhesion to fibronectin, migration, and degranulation but is also critical to mast cell survival. To determine the extent of involvement of signaling pathways in increased apoptosis due to Rac2 deficiency, we examined the activation of PI-3Kinase and its downstream effector, Akt, in response to SCF-stimulation. Although, PI-3Kinase activation in response to SCF stimulation was identical in Rac2−/− compared with wild-type (wt) mast cells, the activation of Akt was completely abolished in Rac2−/− mast cells. Unexpectedly, the level of the proapoptotic protein, Bad was significantly elevated (∼10-fold) in Rac2−/− cells in comparison to wt. In contrast, the level of anti-apoptotic protein Bcl-Xl was significantly reduced (∼10-fold) in Rac2−/− cells in comparison to wt. To confirm that enhanced apoptosis in mast cells was the direct result of Rac2 deficiency, Rac2−/− mast cells were transduced with a retrovirus expressing a wt Rac2 cDNA. As expected, Rac2−/− cells expressing Rac2 as a transgene demonstrated complete correction of all actin-based functions and normal survival of mast cells in response to SCF-stimulation. In addition, the activation of Akt and the level of Bad and Bcl-Xl protein were restored to wt levels. In summary, these data demonstrate that Rac2 not only plays an essential role in hematopoietic cell actin-mediated functions, but also plays a critical role in maintaining the survival of these cells by regulating the activation of Akt and the balance between pro- and anti-apoptotic proteins, Bad and Bcl-Xl.