The palazzo faces Piazza Venezia and Via del Plebiscito; Via del Corso runs along the side.

In 1465 Francesco received a commission from Pius's successor, Paul II, to enlarge the palace that Paul had begun while Cardinal Piccolomini; it became the new papal residence (now the Palazzo Venezia). It was built around the medieval tower at the right of its facade and incorporated within its mass the ancient Church of San Marco. Although Superintendent of the Works, Francesco's exact role is uncertain, but by the time of his death the irregularly shaped 9th-century basilica of S Marco incorporated in the south side of the Palazzo Venezia had been transformed into a symmetrical church.