In the early 15th century, the Venetians also began to expand in Italy, as well as along the Dalmatian coast from Istria to Albania, which was acquired from King Ladislaus of Naples during the civil war in Hungary. Ladislaus was about to lose the conflict and had decided to escape to Naples, but before doing so he agreed to sell his now practically forfeit rights on the Dalmatian cities for a meager sum of 100,000 ducats.

Francesco Foscari - Doge from 1423-1457 Venice exploited the situation and quickly installed nobility to govern the area, for example, Count Filippo Stipanov in Zadar. This move by the Venetians was a response to the threatening expansion of Giangaleazzo Visconti, Duke of Milan. Control over the north-east main land routes was also a necessity for the safety of the trades. By 1410, Venice had a navy of 3,300 ships (manned by 36,000 men) and taken over most of Venetia, including such important cities as Verona (which swore its loyalty in the Devotion of Verona to Venice in 1405) and Padua.

The situation in Dalmatia had been settled in 1408 by a truce with King Sigismund of Hungary but the difficulties of Hungary finally granted to the Republic the consolidation of its Adriatic dominions. At the expiration of the truce, Venice immediately invaded the Patriarchate of Aquileia, and subjected Traù, Spalato, Durazzo and other Dalmatian cities. Slaves were plentiful in the Italian city-states as late as the 15th century. Between 1414 and 1423, some 10,000 slaves were sold in Venice, almost all of whom were "nubile" young women from the Balkans. How Welcome In February 1489, the island of Cyprus, previously a crusader state (the Kingdom of Cyprus), was annexed to Venice.

League of Cambrai, the loss of Cyprus, and Battle of Lepanto

The Ottoman Empire started sea campaigns as early as 1423, when it waged a seven-year war with the Venetian Republic over maritime control of the Aegean, the Ionian, and the Adriatic Seas. The wars with Venice resumed in 1463 until a favorable peace treaty was signed in 1479 just after the troublesome siege of Shkodra. In 1480 (now no longer hampered by the Venetian fleet), the Ottomans besieged Rhodes and briefly captured Otranto. By 1490, the population of Venice had risen to about 180,000 people.J. J. Norwich, A History of Venice, p. 494. War with the Ottomans resumed from 1499 to 1503.

In 1499, Venice allied itself with Louis XII of France against Milan, gaining Cremona. In the same year, the Ottoman sultan moved to attack Lepanto by land, and sent a large fleet to support his offensive by sea. Antonio Grimani, more a businessman and diplomat than a sailor, was defeated in the sea battle of Zonchio in 1499. The Turks once again sacked Friuli. Preferring peace to total war both against the Turks and by sea, Venice surrendered the bases of Lepanto, Durazzo, Modon and Coron.

Venice's attention was diverted from its usual maritime position by the delicate situation in Romagna, then one of the richest lands in Italy, which was nominally part of the Papal States but effectively divided into a series of small lordships which were difficult for Rome's troops to control. Eager to take some of Venice's lands, all neighbouring powers joined in the League of Cambrai in 1508, under the leadership of Pope Julius II. The pope wanted Romagna; Emperor Maximilian I: Friuli and Veneto; Spain: the Apulian ports; the king of France: Cremona; the king of Hungary: Dalmatia, and each of the others some part. The offensive against the huge army enlisted by Venice was launched from France. in Nafplion, Greece, one of many forts that secured Venetian trade routes in the Eastern Mediterranean.

On 14 May 1509, Venice was crushingly defeated at the battle of Agnadello, in the Ghiara d'Adda, marking one of the most delicate points in Venetian history. French and imperial troops were occupying Veneto, but Venice managed to extricate itself through diplomatic efforts. The Apulian ports were ceded in order to come to terms with Spain, and pope Julius II soon recognized the danger brought by the eventual destruction of Venice (then the only Italian power able to face kingdoms like France or empires like the Ottomans). The citizens of the mainland rose to the cry of "Marco, Marco", and Andrea Gritti recaptured Padua in July 1509, successfully defending it against the besieging imperial troops. Spain and the pope broke off their alliance with France, and Venice regained Brescia and Verona from France also. After seven years of ruinous war, the Serenissima regained its mainland dominions west to the Adda river. Although the defeat had turned into a victory, the events of 1509 marked the end of the Venetian expansion.

In 1489, the first year of Venetian control of Cyprus, Turks attacked the Karpasia Peninsula, pillaging and taking captives to be sold into slavery. In 1539 the Turkish fleet attacked and destroyed Limassol. Fearing the ever-expanding Ottoman Empire, the Venetians had fortified Famagusta, Nicosia, and Kyrenia, but most other cities were easy prey. By 1563, the population of Venice had dropped to about 168,000 people. In the summer of 1570, the Turks struck again, but this time with a full-scale invasion rather than a raid. About 60,000 troops, including cavalry and artillery, under the command of Mustafa Pasha landed unopposed near Limassol on 2 July 1570, and laid siege to Nicosia. In an victory on the day that the city fell – 9 September 1570 – 20,000 Nicosians were put to death, and every church, public building, and palace was looted. Word of the massacre spread, and a few days later Mustafa took Kyrenia without having to fire a shot. Famagusta, however, resisted and put up a heroic defense that lasted from September 1570 until August 1571.

The fall of Famagusta marked the beginning of the Ottoman period in Cyprus. Two months later, the naval forces of the Holy League, composed mainly of Venetian, Spanish, and Papal ships under the command of Don John of Austria, defeated the Turkish fleet at Battle of Lepanto. The victory over the Turks, however, came too late to help Cyprus, and the island remained under Ottoman rule for the next three centuries. By 1575, the population of Venice was about 175,000 people, but partly as a result of the plague of 1575–76 dropped to 124,000 people by 1581.

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