Macrophages play critical roles in tissue repair, regeneration, and fibrosis by adopting various phenotypes in response to injury. Inflammatory monocytes and resident tissue macrophages undergo phenotypic and functional changes during tissue repair, influencing its initiation, maintenance, and resolution. Disruptions in macrophage function can lead to aberrant repair, fibrosis, or chronic wounds. Macrophages regulate tissue repair through pro-inflammatory, pro-wound healing, pro-fibrotic, anti-inflammatory, anti-fibrotic, pro-resolving, and tissue regenerating phenotypes. These phenotypes are influenced by signals from the local microenvironment and can be targeted therapeutically. Distinct macrophage populations, such as resident tissue macrophages and recruited monocytes, have different roles in tissue repair and fibrosis. For example, in the liver, yolk sac-derived macrophages and bone marrow-derived monocytes play distinct roles in injury and recovery. In spinal cord injury, pro-inflammatory and reparative macrophage populations are recruited via different chemokine gradients. In cardiac injury, resident macrophages promote recovery, while recruited monocytes may contribute to tissue destruction. Pro-inflammatory macrophages can exacerbate tissue injury by sustaining inflammatory responses, while anti-inflammatory and anti-fibrotic macrophages promote tissue repair and resolution. Therapeutic strategies targeting macrophage function, such as modulating CSF1 signaling or using IL-10 and TGF-β1 to induce anti-inflammatory macrophages, are being explored. Additionally, macrophages are critical for tissue regeneration, as seen in limb regeneration in salamanders and neonatal heart repair. Macrophages also support the survival and function of stem cells and progenitor cells, which are essential for tissue regeneration. In peripheral nerve regeneration, macrophages produce VEGF-α to facilitate nerve repair. Overall, understanding macrophage function and regulation is crucial for developing therapies to improve tissue repair, regeneration, and fibrosis.Macrophages play critical roles in tissue repair, regeneration, and fibrosis by adopting various phenotypes in response to injury. Inflammatory monocytes and resident tissue macrophages undergo phenotypic and functional changes during tissue repair, influencing its initiation, maintenance, and resolution. Disruptions in macrophage function can lead to aberrant repair, fibrosis, or chronic wounds. Macrophages regulate tissue repair through pro-inflammatory, pro-wound healing, pro-fibrotic, anti-inflammatory, anti-fibrotic, pro-resolving, and tissue regenerating phenotypes. These phenotypes are influenced by signals from the local microenvironment and can be targeted therapeutically. Distinct macrophage populations, such as resident tissue macrophages and recruited monocytes, have different roles in tissue repair and fibrosis. For example, in the liver, yolk sac-derived macrophages and bone marrow-derived monocytes play distinct roles in injury and recovery. In spinal cord injury, pro-inflammatory and reparative macrophage populations are recruited via different chemokine gradients. In cardiac injury, resident macrophages promote recovery, while recruited monocytes may contribute to tissue destruction. Pro-inflammatory macrophages can exacerbate tissue injury by sustaining inflammatory responses, while anti-inflammatory and anti-fibrotic macrophages promote tissue repair and resolution. Therapeutic strategies targeting macrophage function, such as modulating CSF1 signaling or using IL-10 and TGF-β1 to induce anti-inflammatory macrophages, are being explored. Additionally, macrophages are critical for tissue regeneration, as seen in limb regeneration in salamanders and neonatal heart repair. Macrophages also support the survival and function of stem cells and progenitor cells, which are essential for tissue regeneration. In peripheral nerve regeneration, macrophages produce VEGF-α to facilitate nerve repair. Overall, understanding macrophage function and regulation is crucial for developing therapies to improve tissue repair, regeneration, and fibrosis.