Unlike in the healthy mammalian retina, macrophages in retinal degenerative states are not solely comprised of microglia but may include monocyte-derived recruits. Recent studies have applied transgenics, lineage-tracing, and transcriptomics to help decipher the distinct roles of these two cell types in the diseasesettings of inherited retinal degenerations and age-related macular degeneration.Literature discussed here focuses on the ectopic presence of both macrophage types in the extracellular site surrounding the outer aspect ofphotoreceptor cells (i.e.,the subretinal space), which is crucially involved in the pathobiology. From these studies we propose a working model in which perturbed photoreceptor states cause microglial dominant migration to the subretinal space as a protective response, whereas the abundant presence ofmonocyte-derived cells there instead drives and accelerates pathology. The latter, we propose, is underpinned by specific genetic and nongenetic determinants that lead to a maladaptive macrophage state. Mononuclear phagocytes (MNPs) are central players in retinal degeneration, as seen in age-related macular degenerationand inherited retinal degeneration.A key feature of retinal degeneration is the invasion of MNPs into the subretinal space (an extracellular site critical for vision).However, it remains debated whether these cells consist of microglia and/or monocyte-derived cells, and what are their respective roles.We argue that in retinal degeneration settingsin mouse models, ‘adaptive’ MNP responses are those in which reactive microglia migrate into the subretinal space and play a role in restricting diseaseprogression.‘Maladaptive’ response, by contrast, are seen, for example, in mice with certain deficiencies in MNP-expressed genes. There, a normally subthreshold insult can result in an abundance of pathogenic monocyte-derived cells in the subretinal space.We further lay out how these adaptive/maladaptive classifications may serve as a conceptual framework to help betterunderstand the complex roles of microglia versus monocytes in the human diseasecontext.