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The Carthaginians established a permanent trading port on the coast at Cartagena, which the Romans called Carthago Nova. For the Carthaginian traders, the mountainous territory was merely the Iberian hinterland of their seacoast empire. During The Roman period Murcia did not exist but its actual borders could have been inside of the province of Hispania Carthaginensis. Under the Moors, who introduced the large-scale irrigation on which Murcian agriculture depends, the province was known as Todmir; it included, according to Idrisi, the 11th century Arab cartographer based in Sicily, the cities of Orihuela, Lorca, Mula and Chinchilla, Spain.

The Kingdom of Murcia became independent as a taifa centered on the Moorish city of Murcia after the fall of the Umayyad Caliphate of Córdoba (11th century). Moorish Taifa of Murcia included Albacete and part of Almería as well. After the battle of Sagrajas in 1086 the Almoravid dynasty swallowed up the taifas and reunited Islamic Spain. Ferdinand III of Castile received the submission of the Moorish king of Murcia in 1243.

In the usual way, the Muslims were evicted from the cities, and Ferdinand's heir Alfonso X of Castile, who benefited from rule over a largely depopulated Murcia, divided the border kingdom in three regions for administrative purposes, entrusted respectively to the concejos de realengo, to the ecclesiastical señores seculares, as a reward for their contributions to the Reconquista and to the Military Orders founded in the 11th century. Alfonso annexed the Taifa of Murcia as King of Murcia and Señorio de Cartagena outright in 1266, and it remained technically a vassal kingdom of Spain until the reforms in the liberal constitution of 1812. Murcia became an autonomous region in 1982.

The Castilian conquest of Murcia was significant because it gave the former access to the Mediterranean for the first time and ended the expansion of the Kingdom of Aragon which had been moving south along the coast.