The Italian Wars, often referred to as the Great Wars of Italy and sometimes as the Habsburg–Valois Wars, were a long series of wars fought between 1494 and 1559 in Italy during the Renaissance. The Italian peninsula, economically advanced but politically divided between several states, became the main battleground for European supremacy. The conflicts involved the major powers of Italy and Europe, in a series of events that followed the end of the 40-years long Peace of Lodi agreed in 1454 with the formation of an Italic League.
The new Pope, Julius II (1503-1513), reversed the policies of the Borgias and exiled Cesare. With France taking over almost all of Northern Italy after defeating Venice at the Battle of Agnadello and Ferdinand of Aragon coming to southern Italy to be crowned King of the Two Sicilies, Julius II planned to "free Italy from the barbarians" and orchestrated the recapture of the peninsula. After Spain recognized the Two Sicilies as a papal fief, Julius II personally led his armed forces at the Battle of Mirandola and subsequently forced the French of Louis XII out of Italy in alliance with Switzerland and the Holy Roman Empire. The sudden death of Julius II led to the restoration of the status quo ante bellum in 1516: the treaties of Brussels and Noyon, arranged by Maximilian I, Holy Roman Emperor and Pope Leo X, recognized French control in the north (excluding the Venetian republic) and Spanish control in the south.
War resumed in 1521 as Pope Leo X and Charles V, Holy Roman Emperor (simultaneously ruler of Austria, the Spanish kingdoms, and the Low Countries) expelled French forces from Milan. Francis I of France reacted by descending in Italy and fighting Imperial forces at the Battle of Pavia (1525), where he was captured and forced to give French territory to the Habsburg Netherlands of Charles V. Following his liberation, Francis I initiated a new war in Italy during which mutinous Germanic troops of lutheran faith sacked Rome (1527) and expelled the Medici from Florence. After ordering the retreat of Imperial troops from the Papal States, Charles V restored the occupied French territory to Francis I on the condition that France abandoned northern Italy ("Peace of the Ladies"). At the Congress of Bologna in 1530, Charles V received the Imperial title of King of Italy by Pope Clement VII. In exchange, the Pope obtained the restoration of the Medici family as the ruling dynasty of Florence.
Following Catholic victories in Vienna and Tunis against the Ottomans, a new congress (1536) was held in Rome between Charles V and Pope Paul III to discuss the hypothesis of an ecumenical council to deal with Protestantism. Despite fears of conciliarism within the curia, Pope Paul III ultimately saw a council as an opportunity to end the Catholic Imperial-French wars in Italy by uniting the anti-calvinist French royalty with the Habsburgs against a common enemy. Indeed, the conflict had resumed at the Lombard-Piedmontese border with the French occupation of the Savoyard state soon after Charles V took the vacant Duchy of Milan. Therefore, Pope Paul III favored the "Peace of Nice" between Francis I and the Emperor (1538) as well as the subsequent "Peace of Crespy" (1544). The Council of Trent began in 1545, but Lutheran princes refused to recognize it with the result of entering a war with the Emperor (quickly lost) and allowing the Pope to dominate the council and initiate the counter-reformation. Around 1547, papal and imperial factions clashed for political supremacy and a series of conspiracies took place in several courts of Italy. The assassination of Pier Luigi Farnese, Duke of Parma and son of the Pope, led to the suspension of the council until Pope Julius III reconvened it with the intention to promote a reconciliation of the defeated Lutherans with Charles V.
In 1551, Henri II of France invaded Tuscany and supported Siena in a war against Florence. In addition, France captured the Three Bishoprics of the Holy Roman Empire with the support of Lutherans and formed an alliance with the Ottoman Empire (who had defeated Charles V in Algiers and Budapest in the 1540s) in order to invade Corsica. Charles V responded by forming an alliance with the Kingdom of England and by suspending the reconciliation with the German lutherans. Florence annexed Siena after victory over the French at the Battle of Scannagallo and the Genoese admiral Andrea Doria recaptured Corsica, but England lost the Pas-de-Calais to France.
Charles VIII of France improved relations with other European rulers in the run up to the First Italian War by negotiating a series of treaties: in 1493, France negotiated the Treaty of Senlis with the Holy Roman Empire; on 19 January 1493, it signed the Treaty of Barcelona with the Crown of Aragon and, later in 1493, the Treaty of Étaples with England.