The economic and political relations between Romans and Greeks on the Eastern shores of the Adriatic has always been a matter of scholarly discussion. Their initial political contact can roughly be placed during the so called First Illyrian War (229 B.C.), when the most significant Greek polis – Issa – placed itself under the protection and guidance of Rome. From that point on, during the Late Republican period the Issaean Greeks became the most loyal and longstanding Roman ally on the Eastern Adriatic. However, although the Issaeans sided with Rome in every major conflict in the area (Illyrian wars, Macedonian wars, the conflicts with the Delmatae, etc.) the position of Issa rapidly changed in the first century B.C. The integration of territory in the Roman system that lead to the establishment of the province of Illyricum, and the beginning of intense Romanisation endangered the existing economic “privileges” of Issaeans and its local Greek allies. The transformation to provincial administration and the massive arrival of Romans and Italics created new circumstances in Illyricum and Issa became a foe rather than an ally of these changes. Therefore, this paper intends to give perspective on several questions regarding the position of Issaean Greeks in Illyricum between the third and first century B.C.: the strategic position of Issa during several Roman military interventions across the Adriatic ; the existence of Roman officials and citizens on the island ; the conflict between Issa and a conventus c. Romanorum in Salona ; and the political and economic position of Issa in Illyricum up until it lost its independence as a consequence of aligning itself against G. Julius Caesar in the Roman Civil War.