Taking over from the Victory/Angel, and well in advance of Byzantine coins, the Mother of God makes her first appearance on imperial seals in the mid-sixth century, perhaps as early as the reign of Justinian I, although the attribution of the Dumbarton Oaks specimen is uncertain. By the reign of Tiberios II Constantine (578–582), the design that would become standard for the early Byzantine period was introduced: the Mother of God, standing and holding before her either a medallion of Christ or Christ himself, and flanked by two crosses. Her appearance coincides with the development of her cult, and especially her status as protectress of Constantinople.
The first change from this design does not occur until a century after Justinian I during the reign of Constantine IV (668–685). Instead of holding Christ before her, the Mother of God now holds him on her left arm. This innovation was not retained by Constantine's son Justinian II during his first reign, but made a return during his second and remained the standard obverse image until 720. The design made a final appearance at the beginning of the ninth century during the reign of Nikephoros I (802–811). Instead of flanking crosses, however, Nikephoros’s design incorporates the cruciform invocative monograms that dominate personal seals of the eighth and ninth centuries.
After Nikephoros, the Mother of God disappears from seals until the reign of Constantine X Doukas (1059–1067). She does appear on two tokens in the Dumbarton Oaks collection: one from the regency of Zoe (914–917) and one from the reign of John I Tzimiskes (969–976). Under John I, who was particularly devoted to her cult, the Mother of God appears on coins as well as on tokens, crowning the usurper, thereby granting him divine protection as well as legitimacy. The divine coronation first appears on the coins of Alexander, who is shown with St. Alexander, and recurs on coins and, less frequently, on seals until the end of the empire. Full-length depictions of the Mother of God are first used on these coronation types beginning under Constantine X, and also appear under Eudokia when she appears alone and orans. Although the Mother of God enthroned was a popular image on the seals of empresses in the late Byzantine period, the only woman to rule the empire at this time was Anna Palaiologina (1341–1347)