The Ottoman conquest during the early years of the 16th century prompted the formation of the Uskoks, which were led by Croatian captain Petar Kružić, also called Prince of Klis.

Citizens fled the town, while the Uskoci retreated to the city of Senj, where they continued fighting the Ottoman army.

[8] The fortress stands along the route by which the Ottomans could penetrate the mountain barrier separating the coastal lowlands from around Split, from Ottoman-held Bosnia.

[8] Although nominally accepting the sovereignty of the Habsburg Emperor Ferdinand, who obtained the Croatian crown in 1527, Kružić and his freebooting Uskoks were a law unto themselves.

[8] Kružić led the defense of Klis, and with his soldiers fought almost alone against the Ottomans, as they repeatedly hurled armies against the fortress.

[2] Pope Paul III claimed some rights in Klis,[Note 2] and in September 1536, there was talk in the Curia of strengthening the defenses of the fortress.

[16] Ferdinand did send aid to Klis and was apparently hopeful of holding the fortress, when the Ottomans again laid siege to it.

[16] There were about 3,000 infantry in the reinforcements, which made a sizeable relief force, that were commanded by Petar Kružić, Niccolo dalla Torre, and a papal commissioner Jacomo Dalmoro d'Arbe.

[16] After Ibrahim's death, Suleiman sent 8,000 men under the command of Murat-beg Tardić (Amurat Vaivoda), a Croatian who had been born in Šibenik, to go and lay siege to Klis fortress (Clissa), and fight against Kružić.

[18] Badly-drilled reinforcements sent by the Habsburgs fled in fear of the Ottomans, and their attempts to re-board their boats at Solin Bay caused many vessels to sink.

[18] After Kružić's death, and with a lack of water supplies, the Klis defenders finally surrendered to the Ottomans in exchange for their freedom, on 12 March 1537.

[2] During the Ottoman wars in Europe, Klis Fortress became an administrative centre or sanjak (Kilis Sancağı) of the Bosnia Eyalet, and would remain so for a century.

[21] On 7 April 1596, Split noblemen Ivan Alberti and Nikola Cindro, along with Uskoci, Poljičani, and Kaštelani irregulars, organized a liberation of Klis.