Approximately 5%–50% of the tumor mass consists of tumor-associated macrophages (TAMs), and increased intratumoral macrophage density correlates with poor prognosis. Due to their high activation plasticity, macrophages can adapt their function according to environmental stimuli. TAMs usually help tumor development by promoting cancer cell survival, modifying extracellular matrix proteins, inducing angiogenesis, assisting cancer spread, and suppressing adaptive immune responses. Macrophages are also intimately involved in the process of tumor cell intravasation. Without malignant mutations and being genetically stable, TAMs are less likely to develop drug resistance and are therefore good therapeutic targets. To date, preclinical studies performing TAMs depletion either with genetic or pharmacologic approaches have shown TAMs as essential in metastasis formation. Identifying, targeting and/or modulating the partners in the TAM–tumor cell interaction or TAM activation status are other valid strategies to prevent or even treat bone metastasis.