Microglia are brain-resident immune cells that play a critical role in the development, maturation, and maintenance of the central nervous system (CNS). A study using a mouse model lacking microglia (Csf1rΔFIRE/ΔFIRE) reveals that while microglia are not essential for the early maturation of other brain cell types, their absence leads to progressive brain pathologies with aging. These include brain calcifications, macroglial reactivity, and white matter damage, resembling features of human CSF1R-related leukoencephalopathy. The thalamus is particularly vulnerable, showing atrophy, neuron loss, vascular alterations, and severe calcification. Transplanting healthy microglia into these brains prevents and reverses many of these pathologies. The study also shows that the absence of microglia leads to dysregulation of macroglial cells, increased glial reactivity, and progressive white matter deterioration. Thalamic calcification is significantly accelerated in the absence of microglia, with calcified regions showing increased interaction with GFAP-positive astrocytes. Vascular alterations are also observed in severely calcified regions of the thalamus, with some calcifications in contact with blood vessels. These findings highlight the critical role of microglia in maintaining brain health and preventing age-related pathologies.Microglia are brain-resident immune cells that play a critical role in the development, maturation, and maintenance of the central nervous system (CNS). A study using a mouse model lacking microglia (Csf1rΔFIRE/ΔFIRE) reveals that while microglia are not essential for the early maturation of other brain cell types, their absence leads to progressive brain pathologies with aging. These include brain calcifications, macroglial reactivity, and white matter damage, resembling features of human CSF1R-related leukoencephalopathy. The thalamus is particularly vulnerable, showing atrophy, neuron loss, vascular alterations, and severe calcification. Transplanting healthy microglia into these brains prevents and reverses many of these pathologies. The study also shows that the absence of microglia leads to dysregulation of macroglial cells, increased glial reactivity, and progressive white matter deterioration. Thalamic calcification is significantly accelerated in the absence of microglia, with calcified regions showing increased interaction with GFAP-positive astrocytes. Vascular alterations are also observed in severely calcified regions of the thalamus, with some calcifications in contact with blood vessels. These findings highlight the critical role of microglia in maintaining brain health and preventing age-related pathologies.