Macrophages are distributed throughout the retina. In the steady state, there is a slow turnover of bone marrow-derived cells in both the inner retinal perivascular location (perivascular macrophages) and within the parenchyma (microglia). The roles of microglia are largely regulatory and mediated, in part, via expression of inhibitory receptors such as CD200R. Although if activated, and alongside the contribution of infiltrating myeloid cells, microglia contribute to the expression of target organ damage during both degeneration and autoimmunity. Macrophage activation and behavioral responses are dependent upon the environmental conditions and signals (danger) that they receive. The result is a balance between governing of regulation and activation of acquired immunity, and facilitation of appropriate responses to danger, including appropriate resolution and healing. Loss of control of macrophage activation may result in undue chronic inflammation where the author’s team further insights into mechanisms have lead to possibilities of therapies to redress the balance. For example, macrophage activation is highly dependent upon myeloid autocrine tumor necrosis factor (TNF) production and the presence of functional TNFR1 signaling that critically defines responses and controls T cell proliferation in the tissue by both maintaining trafficking of myeloid cells to the tissue and generating myeloid suppressor cell phenotype and behavior to counter autoimmune T cell responses.