Age-related macular degeneration (AMD) is the leading cause of legal blindness and visual impairment in individuals over 60 years of age in the Western World. A common morphological denominator in all forms of AMD is the accumulation of microglia within the sub-retinal space, which is believed to be a contributing factor to AMD progression. However, the signaling pathway and molecular players regulating microglial recruitment have not been completely identified. Multiple in-vitro and in-vivo studies, to date, have highlighted the contributions of nuclear receptor ligands in the treatment of inflammation related disorders such as atherosclerosis and Alzheimer’s disease. Given that inflammation and the immune response play a vital role in the initiation and progression of AMD, in this brief review we will highlight some of these studies with a particular focus on the lipid activated “adopted orphan” nuclear receptors, the liver x receptors (LXRs) and the peroxisome proliferator-activated receptors (PPARs). The results of these studies strongly support the rationale that treatment with LXR and PPAR ligands may ameliorate microglial activation in the sub-retinal space and ultimately slow down or reverse the progression of AMD.