From 1502, the Portuguese had waged a relentless struggle against Arab trade in order to win the monopoly of trade in the Indian Ocean. The Mamluks were no match for them in naval resources or firearms so they had turned to the Ottomans for help (c.1509), while the Portuguese offered help to the Safavid Shah Isma’il. The Portuguese threatened to occupy Jedda, Mecca and Medina and exhume the remains of the Prophet, so in 1516 the descendants of the Prophet in Mecca and Medina despatched a delegation to Selim which the Mamluks, who saw themselves as masters of the Holy Cities of Islam, prevented from getting to Istanbul. Selim then made it known he wanted to liberate the Arabs from Mamluk oppression and began to infringe the borders of Mamluk territory, leading troops down the banks of the Euphrates. War was inevitable: in May 1516, the Mamluk Sultan al-Ghawri set off for Aleppo with an army, taking with him the Abbasid Caliph al-Mutawakkil who lived a pensioner at his court. In Aleppo the locals turned against the Mamluks, and they were utterly routed, and al-Ghawri mortally wounded, by the Ottomans. Selim treated the Caliph with deference but took measures to prevent him escaping; al-Mutawakkil and the Mamluk qadis swore allegiance to Selim, marking the dissolution of the Mamluks and allowing Selim to add the rule of Egypt, Syria and Palestine to the Ottoman empire. In 1528, this brought the Ottoman treasury an extra annual revenue of approximately 100 million silver aspers (approx.1.8 million gold pieces).

The protection of the Holy Cities Mecca and Medina and the Pilgrimage routes conferred pre-eminence in the Islamic world: Selim claimed that the Mamluks had been incapable of protecting the pilgrim routes in the Hijaz and that God had entrusted him with the task of bringing order to all lands of Islam, warning he would shortly conquer Safavid Persia, which he considered to be ruled by heretics. At that time the Ottoman Sultan was the ruler of all Muslim lands from the Habsburg frontier to Yemen. Selim died while preparing for an offensive against Rhodes, the gate to the Mediterranean; he was succeeded by his son, the most famous of Ottoman Sultans, Süleyman I, called ‘the Magnificent’ (1520-66).