Macrophages are now routinely categorized into phenotypic subtypes based on gene expression induced in response to cytokine and pathogen-derived stimulation. In the broadest division, macrophages are described as being CAMs (M1 macrophages) or AAMs (M2 macrophages) based on their exposure to TLR and IFN signals or Th2 cytokines, respectively. Despite the prolific use of this simple classification scheme, little is known about the precise functions of effector molecules produced by AAMs, especially how representative the CAM and AAM subtypes are of tissue macrophages in homeostasis, infection, or tissue repair and how plasticity in gene expression regulates macrophage function in vivo. Furthermore, correlations between mouse and human tissue macrophages and their representative subtypes are lacking and are a major barrier to understanding human immunity. Here, we briefly summarize current features of macrophage polarization and discuss the roles of various macrophage subpopulations and macrophage-associated genes in health and disease.