They meet amid debate over whether the Church needs a manager pope to clean up the Vatican or a pastoral pope who can inspire the 1.2 billion faithful at a time of crisis.
Cardinals will begin the day by checking into the Vatican's Domus Sanctae Martae, a modern, industrial-feel hotel on the edge of the Vatican gardens which was first used during a conclave in 2005.
The dean of the College of Cardinals, Angelo Sodano, will lead the celebration of the Pro eligendo Pontificie Mass – the Mass for the election of a pope –inside St Peter's Basilica.
The cardinals will then break for lunch at the hotel and return for the 4.30pm procession into the Sistine Chapel, chanting the Litany of Saints, the hypnotic Gregorian chant imploring the intercession of the saints to help guide the voting.
The first puffs of smoke from the Sistine Chapel chimney should emerge sometime around 6.30pm. Black smoke from the burned ballot papers means no pope. White smoke means the 266th pope has been chosen. If some of the leading contenders fail to reach the 77 votes required for victory in the first few rounds of balloting, any number of surprise names could come to the fore as alternatives.
Whoever it is, the new pope will face a church in crisis.
Clerical sex abuse scandals have soured many faithful and competition from rival evangelical churches in Latin America and Africa has drawn souls away.
Meanwhile, the Church in Scotland is still reeling from the resignation of Cardinal Keith O'Brien who admitted sexual misconduct after complaints by three priests and a former priest.