Macrophages have long been regarded as classic mediators of innate immunity because of their production of proinflammatory cytokines and their ability to induce apoptotic cell death. As a result of such activities and the detrimental long-term effect of kidney inflammation, macrophages principally have been regarded as mediators of glomerular damage, tubular cell death, and the downstream fibrotic events leading to chronic kidney disease. Although this has been the accepted consequence of macrophage infiltration in kidney disease, macrophages also play a critical role in normal organ development, cell turnover, and recovery from injury in many organs, including the kidney. There is also a growing awareness that there is considerable heterogeneity of phenotype and function within the macrophage population and that a greater understanding of these different states of activation may result in the development of therapies specifically designed to capitalize on this variation in phenotype and cellular responses. In this review, we discuss the current understanding of induction and consequences of classic versus alternative macrophage activation and highlight what additional therapeutic options this may provide for the management of both acute and chronic kidney disease as well as renal cancer.