Chemosensory cells in the mucosal surface of the respiratory tract (“brush cells”) utilize the canonical taste transduction cascade to detect potentially hazardous content and trigger local protective and aversive respiratory reflexes upon stimulation. The urogenital tract has been considered to lack this cell type. Recently we newly identified a population of cholinergic epithelial cells in the mammalian urethra that exhibits a structural marker of brush cells (villin) and expresses bitter and umami taste receptors and downstream components of the canonical taste transduction signaling cascade (α-gustducin, phospholipase Cβ2 (PLCβ2), transient receptor potential cation channel melanostatin 5 (TRPM5)). These urethral brush cells respond to stimulation with bitter (denatonium), umami (monosodium glutamate) and uropathogenic Escherichia coli, and release acetylcholine to communicate with other cells. They are approached by sensory nerve fibers expressing nicotinic acetylcholine receptors, and intraurethral application of denatonium reflexively increases activity of the bladder detrusor muscle in anesthetized rats. In order to elucidate cross-species conservation of the urethral chemosensory pathway we investigated the occurrence and molecular make-up of urethral brush cells in placental mammals. We immunohistochemically screened 14 species including humans, at least one in each of the five mammalian taxonomic units primates, carnivora, perissodactyla, artiodactyla and rodentia. Urethral epithelial cells with brush cell shape were immunolabeled in all 14 mammals. These data indicate that urethral brush cells, widespread throughout the mammalian kingdom and evolved not later than about 64.5 million years ago, serve as sentinels, monitoring the chemical composition of the luminal content for potentially hazardous compounds such as bacteria, and initiate protective reflexes counteracting further ingression.