Catecholamines released by sympathetic nerves can activate adrenergic receptors present on nearly every cell type, including myeloid derived suppressor cells (MDSCs). Using in vitro systems and murine tumor models, in wild-type mice and genetically modified (beta2-AR-/-) mice, as well adoptive transfer approaches, we found that the degree of beta2-AR signaling significantly influences MDSC frequency and survival in tumors and other tissues, modulates their expression of immunosuppressive molecules such as arginase-I and PDL-1 and alters their ability to suppress the proliferation of T cells. The regulatory functions of beta-AR signaling in MDSCs were found to be dependent upon STAT3 phosphorylation. Moreover, we observed that the beta2-AR-mediated increase in survival of MDSCs is dependent upon Fas-FasL interactions, and this is consistent with gene expression analyses which reveal a greater expression of apoptosis-related genes in beta2-AR-/- MDSCs. Our data reveals the potential of beta2-AR signaling to increase the generation of MDSCs from both murine and human peripheral blood cells and that the immunosuppressive function of MDSCs could be mitigated by treatment with beta-AR antagonists, or enhanced by beta-AR agonists, strongly supporting the possibility that reducing stress-induced activation of beta2-ARs could help to overcome immune suppression and enhance the efficacy of immunotherapy and other cancer therapies.