A variety of studies have documented increased presence of reactive microglia in the brains of not only Alzheimer’s disease (AD) patients but its transgenic mouse models. Since these cells are often characterized in association with fibrillar Aβ peptide-containing plaques, it has been assumed that plaque interaction provides one stimulus for the phenotype observed. The growing appreciation that microglia phenotype changes with age and that resident immune cells are comingled with blood-derived macrophage has complicated understanding of the behavior of these cells in AD. In addition, comparison of microglia within AD brains and the many rodent models suggests that there are population phenotype differences among these cells within any given brain during disease. Recent immunomodulatory strategies that have been employed, although effective at improving behavioral performance, decreasing Aβ plaque load, and altering immune molecule levels, have not yet resolved the details and dynamics of the microglial and macrophage responses. The heterogeneity of microglial presentation in AD brains and its transgenic mouse models and the outcomes of immunoregulatory efforts will be reviewed below along with the remaining question of how much understanding of microglial behavior is actually required in order to propose a microglia-related therapy for AD.