Microglia are seen as the sentries in the CNS who provide a first line of defense whenever there is injury or disease. Microglia and related perivascular macrophages perform various functions, ranging from immunological surveillance to neuroprotection. Recent work in the aged human brain has provided morphological evidence of structural deterioration of microglia, and work in rodents suggests that microglia are subject to replicative senescence (loss of mitotic ability after repeated rounds of replication). Together these observations raise the possibility that old age, and perhaps other factors (genetic and epigenetic) adversely affect viability and self-renewal capacity of microglia, resulting in the generation of senescent and/or dysfunctional cells. Such attrition of the brain's immune system could contribute to the development of neurodegenerative disease by diminishing glial neuroprotection.