Innate immune cells are critical for transplant response. As an important cellular component of innate immune cells, macrophages are the predominate infiltrated cells in allografts, and macrophage accumulation in allografts is negatively associated with the short- and long-term outcomes of organ transplantation. Macrophages are functionally heterogeneous and plastic. They participate in organ graft rejection through multiple pathways, including antigen presentation, the expression of costimulatory molecules and cytokines, and direct cytotoxicity and injury ability to allografts. However, some macrophage subpopulations, such as regulatory macrophages, can protect allografts from immune rejection and promote transplant immune tolerance with their immune regulatory properties. Although researchers recognize the potential roles macrophages play in allograft injury, they pay insufficient attention to the diverse roles of macrophages in allograft rejection. We herein briefly summarize the distinctive roles of macrophages in acute transplant immune response and the effect of immunosuppressive drugs on macrophages. Greater attention should be paid to the complex and critical function of macrophages in allograft rejection, and more effort should be put into developing immunosuppressive drugs that specifically target macrophages, which would ultimately improve the long-term survival of organ grafts in patients.