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The Palazzo Colonna is a palatial block of buildings built in part over ruins of an old Roman Serapeum, and has belonged to the prestigious Colonna family for over twenty generations.

The first part of the palace dates from the 13th century, and tradition holds that the building hosted Dante in his visit to Rome. The first documentary mention notes that the property hosted Cardinal Giovanni and Giacomo Colonna in the 13th century. It was also home to Cardinal Oddone Colonna before he ascended to the papacy as Martin V (1417–1431).

With his passing, the palace was sacked during feuds, and the main property passed into the hands of the Della Rovere family. It returned to the Colonna family when Marcantonio I Colonna married Lucrezia Gara Franciotti Della Rovere, the niece of pope Julius II. The Colonna"s alliance to the Habsburg power, likely protected the palace from looting during the Sack of Rome (1527).

Starting with Filippo Colonna (1578–1639) many changes have refurbished and create a unitary complex around a central garden. Architects including Girolamo Rainaldi and Paolo Marucelli labored on specific projects. Only in the 17th and 18th centuries were the main facades completed. Much of this design was completed by Antonio del Grande (including the grand gallery), and Girolamo Fontana (decoration of gallery). In the 18th century, the long low facade designed by Nicola Michetti with later additions by Paolo Posi with taller corner blocks (facing Piazza Apostoli) was constructed recalls earlier structures resembling a fortification.

The main gallery (completed 1703) and the masterful Colonna art collection was acquired after 1650 by both the cardinal Girolamo I Colonna and his nephew the Connestabile Lorenzo Onofrio Colonna and includes works by Lorenzo Monaco, Domenico Ghirlandaio, Palma the Elder, Salviati, Bronzino, Tintoretto, Pietro da Cortona, Annibale Carracci (painting of The Beaneater), Guercino, Francesco Albani, Muziano and Guido Reni. Ceiling frescoes by Filippo Gherardi, Giovanni Coli, Sebastiano Ricci, and Giuseppe Bartolomeo Chiari celebrate the role of Marcantonio II Colonna in the battle of Lepanto (1571). The gallery is open to the public on Saturday mornings.

The older wing of the complex known as the Princess Isabelle"s apartments, but once housing Martin V"s library and palace, contains frescoes by Pinturicchio, Antonio Tempesta, Crescenzio Onofri, Giacinto Gimignani, and Carlo Cesi. It contains a collection of landscapes and genre scenes by painters like Gaspard Dughet, Caspar Van Wittel (Vanvitelli), and Jan Brueghel the Elder.

Along with the possessions of the Doria-Pamphilij and Pallavacini-Rospigliosi families, this is one of the largest private art collections in Rome.