Pope Francis, 80, the former Archbishop of Buenos Aires in Argentina, was the first non-European pope in more than 1,200 years and the first Latin American pontiff when he was elected as the 266th head of the Catholic Church four year ago.
On Monday night during an acceptance speech for a major award Charles spoke of the enduring bonds between the UK and Italy less than a week after Theresa May triggered the start of the nation's withdrawal from the European Union.
Charles praised the "partnership'' that has benefited the economies and societies of both countries during an address to a gala dinner in Florence that saw him receive the Renaissance Man of the Year award.
The heir to the throne is on a nine-day tour of Europe with the Duchess of Cornwall which has been widely interpreted as a bridge-building exercise with the continent as Brexit begins.
The last time Charles travelled to the Holy See - the jurisdiction of the Catholic Church in Rome - to meet the Pope was in 2009. He had a private meeting with Pope Benedict XVI.
The royal couple are likely to be greeted by a guard of honour formed by the famous Swiss Guards who protect the Pope.
A traditional exchange of gifts will also take place but it is thought the Duchess will not wear black or a mantilla - a lace veil - as Vatican protocol usually dictates.
Before the meeting with the Pope the royal couple will visit the British School in Rome, while Charles will attend a climate change meeting and visit the English College.
Top ten places to visit in Italy
Top ten places to visit in Italy
This is the largest Basilica of Christianity in the world and the church can hold 20,000 people at any one time. Iconic artists such as Rafael and Michelangelo have both worked on the building, which was consecrated in 1826.
The Gothic Milan Cathedral took nearly six centuries to complete and is the second largest in Italy. The spectacular white and gold cathedral is found at the centre of the city.
The Colosseum in Rome was originally known as the Flavian Ampitheatre and was the site of many Roman gladiator fights. It's thought that construction of this iconic building began between 70 - 80 AD.
The Pantheon in Rome is considered to be one of the best preserved buildings of the Roman empire, it is also one of the most copied ancient buildings. The Pantheon is a combination of Roman and Greek styles with the classic Roman cylindrical structure and outer Grecian colonnade.
The Duomo in Florence is arguably one of the most iconic and recognisable landmarks in the city. Despite the fact the building was started in 1296, the exterior facade was renovated in the Gothic Revival style in the 19th century.
The Doge was the elected ruler of Venice and the palace was once the home of this prominent figure. The palace sits on the famous St Mark's Square alongside Saint Mark's Basilica Cathedral facing on to the iconic Grand Canal.
The statuesque Trevi Fountain stands an astonishing 26 metres high and is one of the most recognisable fountains in the world. The tradition of throwing coins into the Trevi Fountain is a long standing one with a specific meaning. Throwing one coin guarantees your return to Rome, the second promises new love and the third ensures marriage.
Pompeii is the ancient Roman city that fell victim to the monstrous volcano, Vesuvius. The well-preserved remains of the city are considered to be the strongest proof of Roman civilisation. This priceless archaeological site lay preserved under a thick layer of volcanic ash after the eruption.
The Leaning Tower of Pisa is potentially one of the most famous attractions in the world thanks to its recognisable appearance. The clay foundations means that even though the tower stood upright for five years it began to subside heavily to one side later. The tower is also slightly curved as a result of various architects attempting to keep it from falling over.
This famous cathedral in Tuscany is best known for its intricately decorated mosaic floor, which features the work of more than 40 artist. The works of art represent 'sibyls' or scenes from the Old Testament. The tiles are only visible for six to 10 weeks each year, the rest of the time they remain covered to preserve them.