Much like the rest of Italy, Rome is predominantly Roman Catholic, and the city has been an important centre of religion and pilgrimage for centuries, the base of the ancient Roman Religion with the pontifex maximus and later the seat of the Vatican City and the pope. Before the arrival of the Christians in Rome, the Religio Romana (literally, the "Roman Religion") was the major religion of the city in classical antiquity. The first gods held sacred by the Romans were Jupiter, the most high, and Mars, god of war, and father of Rome's twin founders, Romulus and Remus, according to tradition. Other gods and goddesses such as Vesta and Minerva were honoured. Rome was also the base of several mystery cults, such as Mithraism. Later, after St Peter and St Paul were martyred in the city, and the first Christians began to arrive, Rome became Christian, and the St. Peter's Basilica was first constructed in 313 AD. Despite some interruptions (such as the Avignon papacy), Rome has for centuries been the home of the Roman Catholic Church and the bishop of Rome, otherwise known as the pope.
 
The Basilica di Santa Maria Maggiore interior. It is one of the most important churches in the city.

Despite the fact that Rome is home to the Vatican City and St. Peter's Basilica, Rome's cathedral is the Basilica of St. John Lateran, located to the south-east of the city-centre. There are around 900 churches in Rome in total, aside from the cathedral itself, some others of note include: the Basilica di Santa Maria Maggiore, the Basilica of Saint Paul Outside the Walls, the Basilica di San Clemente, San Carlo alle Quattro Fontane and the Church of the Gesu. There are also the ancient Catacombs of Rome underneath the city. Numerous highly important religious educational institutions are also in Rome, such as the Pontifical Lateran University, Pontifical Biblical Institute, Pontifical Gregorian University, and Pontifical Oriental Institute.
 
Basilica of St. John Lateran, the cathedral of Rome

The territory of Vatican City is part of the Mons Vaticanus, and of the adjacent former Vatican Fields, where St. Peter's Basilica, the Apostolic Palace, the Sistine Chapel, and museums were built, along with various other buildings. The area was part of the Roman rione of Borgo until 1929. Being separated from the city on the west bank of the Tiber river, the area was an outcrop of the city that was protected by being included within the walls of Leo IV, later expanded by the current fortification walls of Paul III/Pius IV/Urban VIII. When the Lateran Treaty of 1929 that gave the state its present form was being prepared, the boundaries of the proposed territory was influenced by the fact that much of it was all but enclosed by this loop. For some tracts of the frontier, there was no wall, but the line of certain buildings supplied part of the boundary, and for a small part of the frontier a modern wall was constructed.

The territory includes Saint Peter's Square, separated from the territory of Italy only by a white line along the limit of the square, where it touches Piazza Pio XII. St. Peter's Square is reached through the Via della Conciliazione, which runs from the Tiber River to St. Peter's. This grand approach was constructed by Benito Mussolini after the conclusion of the Lateran Treaty. According to the Lateran Treaty, certain properties of the Holy See that are located in Italian territory, most notably Castel Gandolfo and the major basilicas, enjoy extraterritorial status similar to that of foreign embassies.

In recent years, there has been a significant growth in Rome's Muslim community, mainly due to immigration from North African and Middle Eastern countries into the city. As a consequence of this increase of the local practitioners of the Islamic faith, the commune promoted the building of the largest mosque in Europe, which was designed by architect Paolo Portoghesi and inaugurated on June 21, 1995. Since the end of the Roman Republic Rome is also the center of an important Jewish community, which was once based in Trastevere, and later in the Roman Ghetto. There lies also the major synagogue in Rome, the Tempio Maggiore.