Microglia are emerging as key players in neurodegenerative diseases, such as Alzheimer's disease (AD). Thus far, microglia have rather been known as modulator of neurodegeneration with functions limited to neuroinflammation and release of neurotoxic molecules. However, several recent studies have demonstrated a direct role of microglia in "neuro" degeneration observed in AD by promoting phagocytosis of neuronal, in particular, synaptic structures. While some of the studies address the involvement of the β-amyloid peptides in the process, studies also indicate that this could occur independent of amyloid, further elevating the importance of microglia in AD. Here we review these recent studies and also speculate about the possible cellular mechanisms, and how they could be regulated by risk genes and sleep. Finally, we deliberate on possible avenues for targeting microglia-mediated synapse loss for therapy and prevention. <b>Dual Perspectives Companion Paper: Alzheimer's Disease and Sleep-Wake Disturbances: Amyloid, Astrocytes, and Animal Models by William M. Vanderheyden, Miranda M. Lim, Erik S. Musiek, and Jason R. Gerstner</b> .