The building functions as a guest house for clergy having business with the Holy See, and as the temporary residence of members of the College of Cardinals while participating in a papal conclave to elect a new pope.

Pope Francis has lived in a suite in the building since his election in March 2013, declining to use the papal apartments in the Apostolic Palace.

Pope John Paul II, after participating in two conclaves, decided to make the process more comfortable and less strenuous on the elderly cardinals, and commissioned the construction of Domus Sanctæ Marthæ.

[2] Pope Leo XIII had the St. Martha Hospice built in 1891, on the site now occupied by the Domus, when it was feared that the cholera epidemic of that time might reach Rome.

During World War II the building was used by refugees, Jews, and ambassadors from countries that had severed diplomatic relations with Italy.

[7] At the end of the war, Pope Pius XII greeted 800 Roman children who breakfasted at St. Martha Hospice after receiving their First Communion.

He remained for a time in the room he was assigned by lot at the start of the conclave that elected him and then moved to Suite 201 of Domus Sanctae Marthae.

"[13] He occupies a bedroom furnished with basic necessities, a wooden standing Crucifix, along with a small statue of Our Lady of Luján, the Marian patroness of Argentina, Uruguay, and Paraguay.

Outside his bedroom are two Pontifical Swiss Guards who work day and night shifts, and a statue of Saint Joseph under which the pontiff places prayer requests.