ABSTRACT Synapse elimination is an essential process in the healthy nervous system and is dysregulated in many neuropathologies. Yet, the underlying molecular mechanisms and under what conditions they occur remain unclear. MFG‐E8 is a secreted glycoprotein well known to act as an opsonin, tagging stressed and dying cells for engulfment by phagocytes. Opsonization of cells and debris by MFG‐E8 for microglial phagocytosis in the CNS is well established, and its role in astrocytic phagocytosis, and trogocytosis‐like engulfment of synapses is beginning to be explored. However, MFG‐E8's function in other tissues is highly diverse, and evidence suggests that its role in the nervous system and on synapse elimination in particular may be more complex and varied than opsonization. In this review, we outline the documented direct and indirect effects of MFG‐E8 on synapse elimination, while also proposing potential roles to be explored further, in particular, cytoskeletal reorganization of neurites and glia leading to synapse elimination by various mechanisms. Finally, we demonstrate the need for several open questions to be answered—chiefly, under what conditions might MFG‐E8‐mediated synapse elimination occur in favor of other mechanisms, and when might its activity be dysregulated, increasing unwanted synapse elimination and neurotoxicity? image