Recent clinical and experimental studies demonstrated that the neuroendocrine system accelerates cancer development and progression. To investigate the cellular and molecular mechanism of neuroendocrine regulation of cancer, we have used advanced in vivo imaging technologies to investigate spatial relationships between peripheral neural system, tumor cells and the metastatic microenvironment. We found that chronic activation of the sympathetic nervous system accelerates breast cancer metastasis to distant tissues. Increased metastasis was dependent on beta-adrenergic signaling which induced macrophage recruitment to primary tumors and induced a switch to pro-metastatic and pro-inflammatory gene expression. Our recent studies in orthotopic xenograft models of pancreatic cancer and leukemia showed that activation of neural stress-response pathways similarly accelerated disease progression, suggesting that adrenergic signaling may be a general physiological regulator of cancer progression. These findings raise the possibility that beta-blockade of neural stress response pathways may be a novel therapeutic strategy to slow or prevent metastasis. In addition, we will discuss findings that targeting peripheral nerve fibers may provide therapeutic leverage against metastasis.