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Tumor-associated macrophages are among the most abundant non-cancerous cells in the tumor microenvironment and in many cancers macrophage infiltration into the tumor is associated with poor prognosis. Macrophages contribute to tumor development by promoting angiogenesis and immune suppression, and display remarkable phenotypic heterogeneity in the tumor microenvironment. Therapeutic strategies targeting macrophages that currently are in clinical development are mainly focused on a general depletion of tumor-associated macrophages, either by targeting the CSF-1/CSF-1R axis or by inhibiting macrophage recruitment by blocking CCR2/CCL2 signaling. Despite good pre-clinical response rates the treatment strategies focusing on general macrophage targeting have only shown limited clinical success and new approaches that target specific subsets of tumo-associated macrophages are emerging. This chapter will briefly present the functions and heterogeneity of tumor-associated macrophages and provide an overview of the current state of clinical development for pan-targeting strategies as well as discuss new strategies for targeting specific macrophage subsets for future anti-tumor immunotherapies., Competing Interests: Conflict of interest The authors declare no conflict of interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)