<p>Rejection of solid organ transplants involves both innate and adaptive immune cells. While early acute graft rejection is mainly T-cell-dependent, the late graft rejection, also called chronic rejection, involves diverse innate immune cells, especially macrophages. The fact that most transplants are eventually lost to chronic rejection, for which no effective therapies are currently available, underscores the urgent need for a comprehensive understanding of how macrophages mediate graft loss and therapeutically targeting them to promote long-term graft survival. Phylogenetically, macrophages are the earliest immune cells, whose roles have evolved from simple housekeeping (phagocytosis) to highly specialized and adaptive functions (memory). Here we discuss the phylogeny of macrophages, highlight their noncanonical properties, and review their inherent heterogeneity and functional versatility. We also describe how macrophages promote vascular remodeling and tissue fibrosis in transplanted organs and outline emerging therapeutic strategies for macrophage-targeted interventions in transplantation.</p>