During early embryogenesis, microglia arise from yolk sac progenitors that populate the developing central nervous system (CNS), but how the tissue-resident macrophages are maintained throughout the organism’s lifespan still remains unclear. Here, we describe a system that allows specific, conditional ablation of microglia in adult mice. We found that the microglial compartment was reconstituted within 1 week of depletion. Microglia repopulation relied on CNS-resident cells, independent from bone-marrow-derived precursors. During repopulation, microglia formed clusters of highly proliferative cells that migrated apart once steady state was achieved. Proliferating microglia expressed high amounts of the interleukin-1 receptor (IL-1R), and treatment with an IL-1R antagonist during the repopulation phase impaired microglia proliferation. Hence, microglia have the potential for efficient self-renewal without the contribution of peripheral myeloid cells, and IL-1R signaling participates in this restorative proliferation process. Display omitted •Microglia repopulate within 5 days of depletion•Under defined host conditions, microglia can be replaced by BM cells•Without preconditioning, they renew themselves locally by massive proliferation•IL-1R1 on microglia is involved in self-renewal and maintenance Microglia arise from yolk sac progenitors that populate the developing central nervous system (CNS), but how these cells are maintained in the adult remains unclear. Waisman and colleagues show via a genetic approach that after ablation, microglia repopulation is driven by local progenitors in response to IL-1R signaling.