The regional toponym Mesopotamia was coined in the Hellenistic period without any definite boundaries, to refer to a broad geographical area and probably used by the Seleucids. The term biritum/birit narim corresponded to a similar geographical concept and coined at the time of the Aramaicization of the region. It is however widely accepted that early Mesopotamian societies simply referred to the entire alluvium as kalam in Sumerian (lit. "land"). More recently terms like "Greater Mesopotamia" or "Syro-Mesopotamia" have been adopted to refer to wider geographies corresponding to the Near East or Middle East. The later euphemisms are Eurocentric terms attributed to the region in the midst of various 19th century Western encroachments.
Mesopotamian history extends from the emergence of Urban societies in Southern Iraq in the 5th millennium BC to the arrival of Alexander the Great in the 4th century BC (which is seen as the hallmark of the Hellenization of the Near East, therefore supposedly marking the "end" of Mesopotamia). A cultural continuity and spatial homogeneity for this entire historical geography ("the Great Tradition") is popularly assumed, though the assumption is problematic. Mesopotamia housed some of the world's most ancient states with highly developed social complexity. The region was famous as one of the four riverine civilizations where writing was first invented, along with the Nile valley in Egypt, the Indus Valley in the Indian subcontinent and Yellow River valley in China (Although writing is also known to have arisen independently in Mesoamerica and the Andes).

Mesopotamia housed historically important cities such as Uruk, Nippur, Nineveh, and Babylon as well as major territorial states such as the Akkadian kingdom, Third Dynasty of Ur, and Assyrian empire. Some of the important historical Mesopotamian leaders were Ur-Nammu (king of Ur), Sargon (who established the Akkadian Kingdom), Hammurabi (who established the Old Babylonian state), and Tiglath-Pileser I (who established the Assyrian Empire).