It was only with Epirus falling into the hands of foreign dynasties that the title of despot became applied not to the imperial hierarchy, but to the territory, sometimes to the dismay of the local population.

The first ruler of Epirus to receive the title of despot was Michael II, from his uncle Manuel of Thessalonica in the 1230s, and then again, as a sign of submission and vassalage, from the Nicaean emperor John III Vatatzes.

[8][9] Use of a version of the title despot actually associated with territory began under the rule of the Orsini family, following the extinction of the original Komnenos Doukas dynasty.

[3] Thomas II Preljubović, who was granted Epirus by its previous ruler, claimant Serbian emperor Simeon Uroš, was granted the dignity of despot by Simeon and titled himself as the "Despot of Ioannina" to designate his rule over his capital Ioannina and all of Epirus.

[10] To Carlo, the title of despot meant that he could claim rulership over all of Epirus, not just Ioannina; he notably captured Arta, capital under the Komnenos Doukas and Orsini, in 1416.

To the Byzantines in Constantinople, the granting of the title served more to buffer the lack of actual imperial control in the region, only being a nominal reference to the power previously exercised in Epirus by Greek despots.

[3] This title had also been used by Centurione II Zaccaria, Prince of Achaea, and Carlo might have assumed it in 1418 not as a reference to previous rulers of Epirus, but essentially as a usurpation of Centurione's (his former feudal overlord) title after the Prince of Achaea had suffered devastating losses of territory to the Byzantines in that same year.

This version of the title had even more dangerous implications for Constantinople, as it implied rulership over the Byzantine people themselves rather than territory they considered part of their empire.