Macrophages are critical to the immune response, serving multiple essential roles in maintaining tissue homeostasis and providing immune protection. These cells also interact with and influence the extracellular matrix (ECM) by sensing and responding to its components. Such interactions between macrophages and the ECM are mediated through the secretion and uptake of various biomacromolecules, such as cytokines and the extracellular vesicles, including exosomes and microvesicles. These vesicles are pivotal in regulating cellular behaviors that affect the organism's overall function. Moreover, macrophages are integral to the repair mechanisms that alter tissue structure and functionality during tissue remodeling. This chapter will delineate how macrophages interact with the ECM and discuss potential therapeutic strategies leveraging these interactions. It will conclude with a discussion of the challenges ahead, highlighting the importance of understanding macrophage-ECM dynamics for advancing basic biology and clinical applications.