This study identifies a unique molecular and functional signature of microglia, the resident myeloid cells of the central nervous system (CNS). The authors used gene expression and quantitative proteomic analysis to profile microglia from the CNS and compared them with other immune cell types. They identified 239 genes and 8 microRNAs that were uniquely or highly expressed in microglia compared to other immune cells. This signature was not observed in microglial lines or monocytes recruited to the CNS and was also present in human microglia. The study found that TGF-β is crucial for microglial development and function, as microglia in TGF-β-deficient mice showed reduced numbers and altered morphology. The findings provide insights into microglial biology and suggest potential therapeutic targets for CNS diseases.This study identifies a unique molecular and functional signature of microglia, the resident myeloid cells of the central nervous system (CNS). The authors used gene expression and quantitative proteomic analysis to profile microglia from the CNS and compared them with other immune cell types. They identified 239 genes and 8 microRNAs that were uniquely or highly expressed in microglia compared to other immune cells. This signature was not observed in microglial lines or monocytes recruited to the CNS and was also present in human microglia. The study found that TGF-β is crucial for microglial development and function, as microglia in TGF-β-deficient mice showed reduced numbers and altered morphology. The findings provide insights into microglial biology and suggest potential therapeutic targets for CNS diseases.