The notion that breast cancers can survive in an individual patient in a dormant state only to grow as metastatic disease in the future, is in our view incontrovertibly established. Convincing too is the evidence that surgery to remove the primary tumor often terminates dormancy resulting in accelerated relapses. Accepting that many deaths due to breast cancer might be averted were we to understand the cellular mechanisms underlying escape from dormancy, we have examined the extracellular signals produced by breast cancers derived from women with metastatic breast disease. In this perspective, we explore the role of extracellular nucleotide signaling that we have proposed constitutes a pathological axis from the transformed tumor cell to the endothelium in the service of intravasation, dissemination, extravasation and angiogenesis. A role for the dinucleotide kinase NM23/NDPK (nucleoside diphosphate kinase) secreted by breast tumor cells in the generation of signals that stimulate vascular leakiness, anti-thrombosis, endothelial migration and growth, constitutes a mechanistic basis for escape from latency and offers putative therapeutic targets for breast cancer management not previously appreciated.