Our recent experimental data demonstrated a protective role of beta-blockers against sympathetic nervous system-enhanced breast cancer metastasis. Consistent with these findings, human epidemiological data suggests women with breast cancer who also received beta-blocker treatment for hypertension exhibited better cancer related outcomes including reduced metastasis. However, the relative importance of beta-1 versus beta-2 adrenergic pathways remains unclear. To investigate the role of specific beta-adrenergic pathways in improving breast cancer outcomes, we used beta antagonists CGP20712A and ICI118551 to selectively inhibit beta-1 and beta 2 pathways, respectively, in an orthotopic mouse model of breast cancer metastasis. Selective antagonism of the beta-2 adrenergic pathway reduced distant metastasis to lung and lymph node by 47% (p = 0.03), consistent with the effects of the non-selective beta-blocker propranolol. In contrast, selective beta-1 antagonism alone did not reduce metastasis. Beta-2 antagonism reduced the expression of prometastatic genes including Vegfa and Mmp9 and genes associated with an M2 differentiated macrophage phenotype including Arg1 and Tgfb. These findings identify the beta-2 adrenergic pathway as a potential driver of breast cancer progression. This suggests that pharmacological agents that non-specifically target beta-adrenergic pathways such as propranolol may be more appropriate adjuvant therapies in reducing breast cancer metastasis compared to their more commonly prescribed beta-1 selective blockers such as atenolol and metoprolol.