Originally from Latium, the Farnese are first mentioned in the thirteenth century because of the fights between the quarrelsome feudal lords of the region. Men of arms and action, with no inclination for either diplomacy or politics, they distinguished themselves in the service of other, more powerful, families and managed to build up a considerable territory wedged in the Papal States, between lake Bolsena, the swampy coastland of Maremma and the Tyrrhenian sea, which Paul III later turned into the dukedom of Castro.

Paolo Farnese was the first representative of the house to enter the Church in 1482. In 1509, Pope Julius II granted Cardinal Alessandro Farnese the bishopric of Parma and several more investitures over a short period of time. Those appointments, together with his unscrupulous political manouvres, led the clever bishop to the papal throne on 13 October 1534, with the name of Paul III, the first and only pope in the Farnese family.

On 26 August 1545, Paul III separated the cities and territories of Parma and Piacenza from the Papal States and created a dukedom for his son Pier Luigi. Pier Luigi had an enemy in Charles V of Spain, who plotted his death with Ferrante Gonzaga, governor of Milan: on 10 September 1547 the duke was stabbed to death by a group of city nobles, who thus wanted to avenge the abuses of their new lord.

The murder was however pointless, since power remained in the hands of the Farnese family: Pier Luigi's son Ottavio (1556-1586) transferred the capital of the dukedom from Piacenza to Parma, and after his death the two cities came under the rule of the warrior Alessandro (1586-1592), conqueror of the Flemish provinces which had rebelled against Madrid, and courageous commander in the crucial battle of Lepanto (1571). His successor, Ranuccio I (1592-1622), is best remembered for his cruelty: he ordered the public execution in Parma of more than one hundred people suspected of plotting against him (under Ranuccio I, the dukedom of Parma and Piacenza annexed the territories of Colorno, Sala Baganza and Montechiarugolo).

His son Odoardo (1622-1646) embarked on unsuccessful military campaigns, made the mistake of siding with the French against the Spanish, the pope's traditional allies, and was powerless against the devastations caused by the plague, of which about 13,000 people in Piacenza died, and the incursions of Spanish and German mercenary troops.

The House of Farnese continued its decline under Ranuccio II (1646-1694), who lost the Castro territories, and Francesco (1694-1727), who married the German princess Dorotea Sofia of Neuburg. On his sudden death, he was succeeded by his brother Antonio (1727-1731), the last of the Farnese dukes, a portly man weighed down by the political and military games of the great European powers. The main branch of the dynasty died with him. In 1732, the dukedom of Parma and Piacenza came under the rule of Charles of Bourbon, son of Elisabetta Farnese, Queen of Spain, and Philip V.