The study investigates the origin, fate, and dynamics of macrophages at the boundaries of the central nervous system (CNS). It reveals that CNS macrophages, including perivascular (pvMΦ), meningeal (mMΦ), and choroid plexus (cpMΦ) macrophages, originate from yolk sac precursors during embryonic development and remain a stable population. These macrophages are closely related to microglia but represent a distinct specialized population of tissue macrophages. Unlike microglia, which are derived from early yolk sac precursors, CNS macrophages are not derived from blood-borne monocytes. Instead, they rely on the transcription factor Pu.1 for their development, while myb, Batf3, and Nr4a1 are not required. During autoimmune inflammation, these macrophages undergo extensive self-renewal through local proliferation. The study also shows that while pvMΦ and mMΦ persist in adulthood with minimal exchange with blood cells, cpMΦ exhibit a slower continuous exchange with blood cells. The findings challenge previous assumptions about the origin of CNS macrophages and provide new insights into their transcriptional programs and roles in maintaining CNS homeostasis and responding to inflammation. The study uses a combination of fate mapping, parabiosis, and single-cell RNA sequencing to demonstrate these findings, highlighting the importance of CNS macrophages in immune responses at brain boundaries.The study investigates the origin, fate, and dynamics of macrophages at the boundaries of the central nervous system (CNS). It reveals that CNS macrophages, including perivascular (pvMΦ), meningeal (mMΦ), and choroid plexus (cpMΦ) macrophages, originate from yolk sac precursors during embryonic development and remain a stable population. These macrophages are closely related to microglia but represent a distinct specialized population of tissue macrophages. Unlike microglia, which are derived from early yolk sac precursors, CNS macrophages are not derived from blood-borne monocytes. Instead, they rely on the transcription factor Pu.1 for their development, while myb, Batf3, and Nr4a1 are not required. During autoimmune inflammation, these macrophages undergo extensive self-renewal through local proliferation. The study also shows that while pvMΦ and mMΦ persist in adulthood with minimal exchange with blood cells, cpMΦ exhibit a slower continuous exchange with blood cells. The findings challenge previous assumptions about the origin of CNS macrophages and provide new insights into their transcriptional programs and roles in maintaining CNS homeostasis and responding to inflammation. The study uses a combination of fate mapping, parabiosis, and single-cell RNA sequencing to demonstrate these findings, highlighting the importance of CNS macrophages in immune responses at brain boundaries.