The CD11c enhanced yellow fluorescent protein (EYFP) transgenic mouse was constructed to identify dendritic cells in the periphery (Lindquist et al.[2004] Nat. Immunol. 5: 1243–1250). In this study, we used this mouse to characterize dendritic cells within the CNS. Our anatomic results showed discrete populations of EYFP brain dendritic cells (EYFP bDC) that colocalized with a small fraction of microglia immunoreactive for Mac-1, Iba-1, CD45, and F4/80 but not for NeuN, Dcx, NG2 proteoglycan, or GFAP. EYFP bDC, isolated by fluorescent activated cell sorting (FACS), expressed mRNA for the Itgax (CD11c) gene, whereas FACS anlaysis of EYFP bDC cultures revealed the presence of CD11c protein. Light microscopy studies revealed that EYFP bDC were present in the embryonic CNS when the blood–brain barrier is formed and postnatally when brain cells are amenable to culturing. In adult male mice, EYFP bDC distribution was prominent within regions of the CNS that 1) are subject to structural plasticity and neurogenesis, 2) receive sensory and humoral input from the external environment, and 3) lack a blood–brain barrier. Ultrastructural analysis of EYFP bDC in adult neurogenic niches showed their proximity to developing neurons and a morphology characteristic of immune/microglia cells. Kainic acid-induced seizures revealed that EYFP bDC responded to damage of the hippocampus and displayed morphologies similar to those described for seizure-activated EGFP microglia in the hippocampus of cfms (CSF-1R) EGFP mice. Collectively, these findings suggest a new member of the dendritic cell family residing among the heterogeneous microglia population. J. Comp. Neurol. 508: 687–710, 2008.© 2008 Wiley-Liss, Inc.