Alzheimer’s disease (AD) is the health challenge of our generation. The majority of AD cases are of late onset and result from the interaction of many genes and nongenetic risk factors, of which the most important is aging. Emerging genetic studies of late-onset AD implicate the brain’s resident immune cells, microglia, in the pathogenesis of AD. In fact, more than half the risk genes associated with late-onset AD are selectively expressed in microglia and peripheral myeloid cells, two cell types associated with the brain’s immune system; yet, we know shockingly little about their biology and how they contribute to AD pathogenesis. Under normal conditions, microglia actively survey the brain; they are highly sensitive to changes caused by injury, infection or other abnormalities. In this role, they can be beneficial by removing toxic proteins and cellular debris, but they also can promote detrimental forms of neuroinflammation leading to inappropriate and damaging synapse loss—one of the earliest changes in the AD brain, and the strongest correlate of cognitive decline.