So far, there are no clear frontrunners, but two American cardinals are getting some special attention.
Cardinals from around the world gathered for the last congregation meeting ahead of the conclave. It was the last chance to hear speeches and discuss issues before the cardinals enter the Sistine Chapel to choose the next leader of the Roman Catholic Church in secrecy.
The big debate is whether the next leader should be a manager pope to clean up the Vatican or a pastoral pope who can inspire the 1.2 billion Catholics around the world during a time of crisis.
Two cardinals from the U.S. are considered frontrunners: New York's Timothy Dolan, an upbeat defender of catholic orthodoxy, and Boston's Sean Patrick O'Malley, known for how he handled the priest abuse scandal.
Other contenders include Italy's Cardinal Angelo Scola, who was also in the running eight years ago when Benedict was elected. There's also Brazil's Cardinal Odilo Scherer, known for his tweeting and appearances on Brazil's most popular late-night talk show. There are a dozen other names being tossed around.
After Monday's meeting, the conclave staff, the only people who will be allowed in the conclave other than the cardinals, gathered at the Vatican to swear an oath of secrecy.
In preparation for the historic process, authorities are taking no chances with security and have deployed snipers and canines around the Vatican.
The cardinals will move into the Santa Marta residence in the morning. In the afternoon, there will be a procession from the Pauline Chapel to the Sistine Chapel with the cardinals singing. Once inside the Sistine Chapel, they swear an oath. The chapel doors will close with the cardinals inside.
"It was a time of quiet, a lot of time of reflection," said Monsignor Kevin Irwin of Catholic University of America. "They do things graciously, splendidly, slowly, with great decorum."
The conclave will end when a cardinal receives 77 out of a possible 115 votes. Puffs of smoke from the Sistine Chapel chimney will indicate the results. Black smoke from the burned ballot papers means no pope. White smoke means the 266th pope has been chosen.
Whoever it is, the new pope will face a church in crisis. Benedict XVI spent his eight-year pontificate trying to revive Catholicism. With the recently uncovered cases of sex abuse and other issues ruining the church's image, many Catholics say they hope the next pope can lead the church out of turmoil.
"I hope [for] somebody who will really take care of our church and people, and somebody who's really up to date and can feel the need of the people and the church," said church member Zoilo Roldan.
In Los Angeles, the Cathedral of Our Lady of the Angels hosted an all-night prayer vigil for the election of the next pope. Every hour starting at 7 p.m., there will be a recitation of the rosary and other prayers supporting the cardinals making this historic decision.