We have shown that activation of the sympathetic nervous system (SNS) alters the bone marrow environment and causes bone loss in mice, via some of the same signaling molecules that have been implicated in breast cancer metastasis to bone. In addition, chronically depressed patients do not seem to benefit from newly developed treatments for cancer and present with shorter survival. Because severe depression and chronic stress stimulate sympathetic outflow, we hypothesized that SNS activation induced by psychosocial factors remodels the bone marrow environment to make it a fertile soil for breast cancer cells, thereby promoting disseminating cancer cell establishment in the skeleton and leading to reduced survival. A series of experiments in preclinical models of bone metastasis supported this hypothesis, identified RANKL as a SNS-induced cytokine promoting breast cancer cell migration and establishment in bone, and showed that the β-blocker propranolol could reduce the skeletal dissemination of cancer cells. Retrospective clinical studies also suggest a beneficial effect of sympathetic blockade in term of less advanced disease at diagnosis, lower cancer-specific mortality, longer disease-free survival and reduced metastasis development and tumor recurrence, particularly in patients that have taken β-blockers before diagnosis. Therefore, β-blockers or therapies normalizing sympathetic tone might be beneficial as early adjuvant therapies to limit skeletal metastases and to improve prognosis in patients with breast cancer.