Macrophages play a central role in infections, as a target for pathogens and in activation of the immune system. Interleukin-10 (IL-10), a cytokine produced by macrophages, is a potent immunosuppressive factor. Some intracellular pathogens specifically target macrophages for infection and use IL-10 to dampen the host immune response and stall their elimination from the host. Certain viruses induce production of cellular IL-10 by macrophages, whereas other viruses encode their own viral IL-10 homologs. Additionally, specific bacteria, including several Mycobacteria spp. and Listeria monocytogenes, can survive and replicate in macrophages while inducing cellular IL-10, highlighting a potential role for IL-10 of macrophage origin in the immunosuppressive etiology of these pathogens. Thus, the exploitation of IL-10 appears to be a common mechanism of immunosuppression by a diverse group of intracellular pathogens that can infect macrophages.