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The Port of 60 Ships, Sexaginta Prista, was the grandiose name given to the key fortress built here by the Romans, around AD 69–70. From its position high on a bluff, the fortress stood guard over the Danube – the traditional border between the empire and the barbarian hordes – and ensured safe passage for commercial ships. Byzantine Emperor Justinian improved the fortress in the 6th century, but invading Slavic tribes destroyed it soon afterwards. The chronic Slavic raids caused most of Ruse’s inhabitants to move to Cherven, 35km south and now within the Rusenski Lom Nature Park.

Ruse remained relatively forgotten during the First (681–1018) and Second (1185–1396) Bulgarian Empires. Its complete destruction by the invading Ottomans in the 14th century presaged, however, a period of unprecedented greatness. A reforming Turkish district governor, Midhat Pasha, rebuilt and revitalised the town, known to the Turks as Roustchouk. It developed great economic and cultural importance and, in 1866, became the first station on the first railway in the entire Ottoman Empire, linking the Danube with the Black Sea at Varna.

Ruse also became a centre for anti-Turkish agitation during the 19th-century revolutionary period, when Bucharest, just a few hours to the north, was the headquarters of the Bulgarian Central Revolutionary Committee. By the end of the Russo-Turkish War (1877–78), Ruse was the largest, most prosperous city in Bulgaria; the legacy of those halcyon days lingers on in the lovely turn-of-the-century architecture found across the city centre.

Although Ruse would see its stature diminish as Sofia grew in prominence in the early 20th century, and the area suffered environmentally due to Romanian heavy industry across the river during Soviet times, a revitalisation has been occurring since the early 1990s, when UN economic sanctions on wartime Yugoslavia caused considerable economic trade to be rerouted from Vidin to Ruse.