Isolated teeth of Melissiodontinae from two Eocene and four Oligocene localities in southeastern Serbia are described. One new genus and two new species are named. The study of the derived morphology of the cheek teeth and of the contrastingly primordial microstructure of the tooth enamel of this diverse material provides a glimpse into the early history of the subfamily. The supposedly Asian murid ancestor of the Melissiodontinae seems to have reached the Serbian-Macedonian land area during the early or middle Eocene, which is shortly after the split up of the Muridae and Dipodidae and before the ‘Grande Coupure’ of central and Western Europe. We interpret the rapid consequent specialisation of the morphology of the chewing apparatus of the Melissiodontinae as an adaptation to feeding on small invertebrates on the floor of the Eocene forest.