Francesco's education was sponsored by his uncle. He took a doctorate in law at the University of Perugia.
Pope Pius II promoted Francesco's career in the Church, naming him Archbishop of Siena when he was 21 years old.
The following year, the pope made Francesco a cardinal, and during his pontificate, he assigned him important posts like cardinal protector of England and Germany. Francesco's fluency in German enabled him to be effective in foreign negotiations.
When Pope Pius II left Rome to lead a Crusade against the Turks in 1474, he put Francesco in charge of Rome and the Papal States.
Under Pope Paul II, Cardinal Francesco Piccolomini acted as papal legate (representative) to Germany.
Although Francesco did undertake a few foreign missions for Popes Innocent VIII and Alexander VI, he generally avoided Rome during their pontificates.
Cardinal Piccolomini was a man of principles. He was one of the five cardinals who refused to sell their votes in the election of Alexander VI, and he had been the only cardinal to protest Alexander's transferring part of the Papal States to his family.
Cardinal Francesco Piccolomini founded the Piccolomini Library, which is located next to the left transept arm. The library was endowed with the books and manuscripts collected by Pius II before he was elected pope.
For the library's decoration, Cardinal Piccolomini commissioned Pinturicchio to fresco the walls with scenes from his uncle's career, including his pre-clerical period as a diplomat for the Emperor Frederick III.
The figures in all the scenes are in the same scale, which contributes to the cycle's unity.
The ten scenes are painted on three of the walls of a room two vaults wide and four vaults deep.
The chronological series begins with the Departure of Aeneas Silvio Piccolomini for the Council of Basel, which is the first of four scenes on the wall to the left of the entrance wall. At the end of the room are scenes showing his uncle introducing Eleonora of Portugal to Frederick III and receiving the cardinal's hat from Pope Callistus III.
Pope Pius III was elected as a compromise candidate since none of the three leading candidates could achieve a majority vote. The leading candidates were Cardinal Giuliano della Rovere, who was Pope Sixtus IV's nephew, Cardinal Ascanio Sforza, who was the brother of the former dukes of Milan, and Cardinal Georges d'Ambroise, who was a minister of King Louis XII of France.
At the time of his election, the pope, who was in poor health in general, was experiencing an acute attack of gout and was unable to participate in all of the customary ceremonies.
Pope Pius III died less than a month after his election. His death was attributed to a leg ulcer, but there were also rumors that it was caused by poison arranged by Pandolfo Petrucci, the governor of Siena, whom the pope had criticized as corrupt.
Pope Pius' untimely death was unfortunate for the Church because it seems likely that he would have initiated the process of reform that it so desperately needed.