Ephrins are cell-membrane-bound ligands for Eph receptor tyrosine kinases and regulate a variety of developmental processes. In order to investigate the potential roles of the ephrin-Eph system in tooth formation, we studied the cellular mRNA expression of Ephrin-A1-A5 and EphA2, EphA3, EphA4, EphA7, and EphA8 receptors during embryonic histomorphogenesis of the mouse first molar (embryonic days 11.5-18.5). Ephrin-A1, ephrin-A5, EphA2, EphA3, EphA4, and EphA7 were expressed in the tooth germ at the epithelial thickening stage, and later, ephrin-A1, ephrin-A5, EphA2, EphA4, and EphA7 showed distinct expression patterns in the enamel organ undergoing epithelial folding morphogenesis. Prior to birth, ephrin-A1, ephrin-A5, EphA2, and EphA4 transcripts were present in the cuspal area of the dental papilla including the preodontoblasts. In addition, ephrin-A1 and ephrin-A5 were seen in the forming blood vessels and alveolar bone, respectively. In contrast, ephrin-A2, ephrin-A3, and ephrin-A4 showed ubiquitous expression during odontogenesis, whereas EphA8 transcripts were not observed. During dental trigeminal axon pathfinding (embryonic days 12.5-13.5), ephrin-A2, ephrin-A4, and ephrin-A5 were evenly distributed in the trigeminal ganglion, whereas EphA7 was expressed in a subset of ganglion cells. These results suggest regulatory roles for ephrin-A/EphA signaling in the formation of the tooth organ proper and its supporting tissues.