The Republic of Dubrovnik is a unique phenomenon not only in the history of the eastern Adriatic but also in the broader Mediterranean context. The international position of Dubrovnik over the centuries needs to be considered in the context of often very intricate relations and policies of those powers whose dynamic interdependencies, each in their own way, touched and shaped the position of the Republic, equally within the Adriatic-Mediterranean, as well as within a geopolitical framework that includes South-Eastern Europe. The paper deals with the positions of the Dubrovnik Republic and the Levant within the context of the truly turbulent 16th century. In spite of the defined conditions that came from the Dubrovnik vassal status within the Ottoman Empire, additional diplomatic effort was needed to maintain the crucially important trade positions in this part of the Mediterranean, which was disturbed by the new geopolitical constellation of the 16th century.