The decipherment of Mesopotamian cuneiform begins with the discovery of the cuneiform inscriptions at Persepolis. The site was visited by Europeans from the Renaissance on, but it was not until the late eighteenth century that the first accurate copies of the inscriptions were made by a Danish adventurer, Carsten Niebuhr. A number of people had attempted to decipher these texts since they had been discovered, and the most important of these is arguably the German schoolteacher Georg Grotefend, who, in 1802, noticed a recurring pattern in the signs. Due to his familiarity with the later Sassanian inscriptions and with the works of Herodotus, Grotefend correctly deduced that these patterns likely read "Xerxes, great king, king of kings, son of Darius, king of kings" and "Darius, great king, king of kings, son of Hystaspes." However, it was not until Niels Louis Westergaard's and Edward Hincks' major breakthroughs in 1845 and 1846, respectively, that the Persepolis inscriptions could begin to be more fully understood. Hincks continued to make progress in deciphering the Old Persian cuneiform script for the next few years and also began examining cuneiform inscriptions from elsewhere in the ancient Near East, particularly Mesopotamia.

The next significant leap in the decipherment of Mesopotamian cuneiform came from work on the trilingual Bīsitūn inscription. Henry Creswicke Rawlinson, a British army officer stationed in Baghdad, made the first accurate copies of this inscription, which are engraved on a nearly inaccessible high cliff overlooking a valley in Bisitun, Iran. The fact that this inscription included three versions of the same text written in Old Persian, – already satisfactorily deciphered – Elamite, and Babylonian was arguably the most significant factor in the decipherment of Mesopotamian cuneiform.

On 19 January, 1850, Rawlinson presented a preliminary translation, – though without a copy of the text or a transliteration – of what is now referred to as the Black Obelisk, recently brought back to England from Nimrud by Layard. The text on this Neo-Assyrian black limestone bas-relief obelisk refers to the deeds and military conquests of Shalmaneser III (858-824 BC). The identification of the Biblical king Jehu in this text was made by Hincks, who published his own translation of the text in December 1851. By the end of the 1850s, Hincks and Rawlinson had successfully provided a working decipherment of Mesopotamian cuneiform.