The aim of this paper is to provide an overview of the geopolitical status of the Upper Tigris area in antiquity, with a special focus on the period between ca. 401 BCE and the 6th century CE. Despite the popular impression that this area had a distinctly Armenian character, a closer look at its history shows that it was rather a territory with many local geopolitical entities that many neighboring countries periodically fought to possess. This area was strategically significant as a transit region located on the crossroads of important long-distance communication lines. Likewise, its natural resources were undoubtedly crucial to the neighboring countries. Indeed, powerful neighbors around the Upper Tigris area, including Armenia, the Iranian kingdoms of the Parthians and Sasanians, and Rome, sought to control this area, which was often located on the fringes of their states and as such was inevitably doomed to be contested by these empires onmany occasions. This situation can be acutely seen in the conflict between Rome and the Iranian kingdoms of the Parthians and Sasanians, when northern Mesopotamia became a real battleground between the competing empires. In particular, the paper will sketch the development of the geopolitical status of several small geopolitical entities in this region—Sophene, Osrhoene, Gordyene, and Adiabene.