Macrophages are ubiquitous cells physiologically involved in a variety of processes including pathogen destruction, inflammation, tissue repair and remodeling. They have a highly plastic phenotype and their functional polarization is determined by cytokines and factors found within local microenvironments. The role of macrophages during tumor development is ambiguous. At late stages, tumor-associated macrophages are known to produce molecules directly promoting tumor growth, invasion, and metastasis; the so called “myeloid-derived suppressor cells” also suppress the adaptive anti-tumor immune response. However, if properly activated, macrophages may control initial tumor development, and pilot studies in cancer patients suggest that adoptive transfers could be beneficial as adjuvant treatment in patients with minimal residual disease. Indeed, a limited tumor mass will probably be insufficient to educate macrophages into a suppressive phenotype. Thus, the macrophage effect in vivo may be determined by a variety of factors including the tumor type and stage, the degree of macrophage infiltration and their functional polarization. Unfortunately, the in vivo mechanisms responsible for the anti-tumor activity of macrophages are still unclear. Current promising strategies to target tumor macrophages in vivo include pharmacological agents capable to re-polarize them towards a classically activated phenotype or to inhibit their suppressive properties.