Macrophages play a critical role in the tumor microenvironment, influencing angiogenesis, extracellular matrix remodeling, cancer cell proliferation, metastasis, and immunosuppression. However, when appropriately activated, macrophages can mediate phagocytosis of cancer cells and cytotoxic tumor killing, and engage in effective bidirectional interactions with components of the innate and adaptive immune system. Therefore, they have emerged as therapeutic targets in cancer therapy. Macrophage-targeting strategies include inhibitors of cytokines and chemokines involved in the recruitment and polarization of tumor-promoting myeloid cells as well as activators of their antitumorigenic and immunostimulating functions. Early clinical trials suggest that targeting negative regulators (checkpoints) of myeloid cell function indeed has antitumor potential. Finally, given the continuous recruitment of myelomonocytic cells into tumor tissues, macrophages are candidates for cell therapy with the development of chimeric antigen receptor effector cells. Macrophage-centered therapeutic strategies have the potential to complement, and synergize with, currently available tools in the oncology armamentarium. The tumor microenvironment (TME) provides an essential ecological niche for cancer initiation and progression. Inflammatory cells and mediators are key universal components of the TME, and tumor-associated macrophages (TAMs) have served as a paradigm for the connection between inflammation and cancer. The construction and orchestration of an inflammatory TME can be driven by genetic events that cause cell transformation and progression (the so-called intrinsic pathway) and by inflammatory conditions that predispose to neoplasia (the extrinsic pathway) such as inflammatory bowel disease. There is considerable diversity in the inflammatory components of the TME in cancers from different tissues. However, infiltration of myelomonocytic cells, specifically monocytes, macrophages and dendritic cells, represents a common denominator of cancers, irrespective of their origin and localization. Among myelomonocytic cells, macrophages are double-edged swords with dual potential in cancer, a reflection of their plasticity in response to environmental cues. Macrophages have the potential to kill tumor cells, mediate antibody-dependent cellular cytotoxicity and phagocytosis, elicit vascular damage and tumor necrosis, and activate innate or adaptive lymphoid cell-mediated mechanisms of tumor resistance. By contrast, in most established tumors, macrophages contribute to cancer progression and metastasis by various mechanisms, including promotion of cancer cell survival and proliferation, angiogenesis, and suppression of innate and adaptive immune responses. Macrophages have an important role in the antitumor activity of chemotherapy, radiotherapy and monoclonal antibodies (mAbs) by mediating tumoricidal activity and eliciting adaptive immune responses. Moreover, they are an important target of current checkpoint blockade immunotherapy by expressing inhibitory counter-receptors (such as PDL1 and PDL2), thus suppressing adaptiveMacrophages play a critical role in the tumor microenvironment, influencing angiogenesis, extracellular matrix remodeling, cancer cell proliferation, metastasis, and immunosuppression. However, when appropriately activated, macrophages can mediate phagocytosis of cancer cells and cytotoxic tumor killing, and engage in effective bidirectional interactions with components of the innate and adaptive immune system. Therefore, they have emerged as therapeutic targets in cancer therapy. Macrophage-targeting strategies include inhibitors of cytokines and chemokines involved in the recruitment and polarization of tumor-promoting myeloid cells as well as activators of their antitumorigenic and immunostimulating functions. Early clinical trials suggest that targeting negative regulators (checkpoints) of myeloid cell function indeed has antitumor potential. Finally, given the continuous recruitment of myelomonocytic cells into tumor tissues, macrophages are candidates for cell therapy with the development of chimeric antigen receptor effector cells. Macrophage-centered therapeutic strategies have the potential to complement, and synergize with, currently available tools in the oncology armamentarium. The tumor microenvironment (TME) provides an essential ecological niche for cancer initiation and progression. Inflammatory cells and mediators are key universal components of the TME, and tumor-associated macrophages (TAMs) have served as a paradigm for the connection between inflammation and cancer. The construction and orchestration of an inflammatory TME can be driven by genetic events that cause cell transformation and progression (the so-called intrinsic pathway) and by inflammatory conditions that predispose to neoplasia (the extrinsic pathway) such as inflammatory bowel disease. There is considerable diversity in the inflammatory components of the TME in cancers from different tissues. However, infiltration of myelomonocytic cells, specifically monocytes, macrophages and dendritic cells, represents a common denominator of cancers, irrespective of their origin and localization. Among myelomonocytic cells, macrophages are double-edged swords with dual potential in cancer, a reflection of their plasticity in response to environmental cues. Macrophages have the potential to kill tumor cells, mediate antibody-dependent cellular cytotoxicity and phagocytosis, elicit vascular damage and tumor necrosis, and activate innate or adaptive lymphoid cell-mediated mechanisms of tumor resistance. By contrast, in most established tumors, macrophages contribute to cancer progression and metastasis by various mechanisms, including promotion of cancer cell survival and proliferation, angiogenesis, and suppression of innate and adaptive immune responses. Macrophages have an important role in the antitumor activity of chemotherapy, radiotherapy and monoclonal antibodies (mAbs) by mediating tumoricidal activity and eliciting adaptive immune responses. Moreover, they are an important target of current checkpoint blockade immunotherapy by expressing inhibitory counter-receptors (such as PDL1 and PDL2), thus suppressing adaptive