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 be pro-infammatory and cytotoxic (M1) or anti-inflammatory and tumor growth promoting (M2). TAMs usually resemble M2 type macrophages and help the tumor development by promoting cancer cell survival, modifying extracellular matrix proteins, inducing angiogenesis, assisting tumor cell progression 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 the date, pre-clinical studies performing TAMs depletion either with genetic (mice models Csf1op/op and MaFIA) or pharmacologic approaches (liposomal clodronate) have shown TAMs to be essential in metastasis formation. Identifying and targeting the partners in the TAM–tumor cell interaction (e.g. CSF-1 antibody, hyaluronan synthase 2 inhibition, α₄-integrin antibody) or modulating TAM polarization from M2 to M1 (e.g. zoledronate, COX-2 inhibition, mifamurtide) are other valid strategies to prevent or treat bone metastasis.