The Notch signaling pathway regulates several distinct cellular programs that are indispensible for proper embryonic development and maintenance of adult tissue homeostasis. Among the various organs of the human body, the pathway has an important role in the bone microenvironment, managing cell-fate decisions in two bone-specific cells. Significantly, pathological activation of the Notch pathway in these cells by metastatic tumor cells promotes osteolytic colonization of the bone. Armed with this knowledge, disruption of the Notch pathway, and other bone microenvironment signaling components that facilitate Notch-mediated bone metastasis, may serve as a viable therapeutic intervention in this aggressive, incurable disease.