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The integration of biomaterials in medical applications triggers the foreign body response (FBR), a multi-stage immune reaction characterized by the formation of foreign body giant cells (FBGCs). Originating from the fusion of monocyte/macrophage lineage cells, FBGCs are pivotal participants during tissue-material interactions. This review provides an in-depth examination of the molecular processes during FBGC formation, highlighting signaling pathways and fusion mediators in response to both exogenous and endogenous stimuli. Moreover, a wide range of material-specific characteristics, such as surface chemical and physical properties, has been proven to influence the fusion of macrophages into FBGCs. Multifaceted biological activities of FBGCs are also explored, with emphasis on their phagocytic capabilities and extracellular secretory functions, which profoundly affect the vascularization, degradation, and encapsulation of the biomaterials. This review further elucidates the heterogeneity of FBGCs and their diverse roles during FBR, as demonstrated by their distinct behaviors in response to different materials. By presenting a comprehensive understanding of FBGCs, this review intends to provide strategies and insights into optimizing biocompatibility and the therapeutic potential of biomaterials for enhanced stability and efficacy in clinical applications. STATEMENT OF SIGNIFICANCE: As a hallmark of the foreign body response (FBR), foreign body giant cells (FBGCs) significantly impact the success of implantable biomaterials, potentially leading to complications such as chronic inflammation, fibrosis, and device failure. Understanding the role of FBGCs and modulating their responses are vital for successful material applications. This review provides a comprehensive overview of the molecules and signaling pathways guiding macrophage fusion into FBGCs. By elucidating the physical and chemical properties of materials inducing distinct levels of FBGCs, potential strategies of materials in modulating FBGC formation are investigated. Additionally, the biological activities of FBGCs and their heterogeneity in responses to different material categories in vivo are highlighted in this review, offering crucial insights for improving the biocompatibility and efficacy of biomaterials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)