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Systemic factors including cytokines, cell-free nucleic acids, microvesicles, and platelets are appreciated as important regulators of adenocarcinoma progression. Research findings using pre-clinical mouse models have revealed that many such systemically acting factors are either secreted by or responsive to peripheral tumors and impact bone and bone marrow (collectively referred to as the bone microenvironment) to initiate processes that ultimately govern disease progression, even in the absence of detectable bone metastases. In some cases, cancer-driven modulation of the bone microenvironment involves mobilization of bone marrow hematopoietic and mesenchymal cells into the circulation that are subsequently recruited into peripheral tissues and tumors. In other cases, systemic factors alter bone marrow cell (BMC) differentiation and/or gene expression to render the BMCs pro-tumorigenic even prior to their mobilization into the circulation. Given their effect on the bone microenvironment, it stands to reason that such systemic factors might also influence metastases in the bone; however, this hypothesis remains to be comprehensively tested. Here, we briefly review what is known, and not known, about systemic factors that regulate the bone microenvironment and thereby influence bone metastases. We also pose a number of currently unanswered questions in this active area of research. A better understanding of systemic processes that influence bone metastasis should aid discovery of therapeutic approaches that aim to eradicate or reduce disease burden in the bone, which is the cause of significant patient mortality and morbidity and is currently incurable.