There is a close spatial and temporal relationship between macrophage accumulation and active renal fibrosis in human and experimental kidney disease. Different subtypes of macrophages have been identified. Pro-inflammatory M1-type macrophages can cause acute tissue injury, whereas pro-fibrotic M2-type macrophages can drive the fibrotic response during ongoing tissue injury. Macrophages induce fibrosis through the recruitment, proliferation, and activation of fibroblasts. In addition, there is accumulating evidence that supports a direct fibrotic role for macrophages via transition into myofibroblasts in a process termed macrophage–myofibroblast transition (MMT). Co-expression of macrophage and myofibroblast antigens identifies the MMT process both in human and experimental fibrotic kidney disease. This co-expression identifies a bone marrow–derived monocyte/macrophage source for a substantial proportion of the myofibroblast population present during renal fibrosis. This postulated MMT pathway represents a new mechanism linking macrophage-rich acute inflammation with the progression to myofibroblast accumulation and renal fibrosis. Further studies are required to identify the molecular mechanisms regulating the MMT process, which macrophage populations can undergo MMT, and to define the functional contribution of MMT to active collagen deposition during renal fibrosis.