He was appointed Administrator of the diocese of Saint-Pons-de-Thomières on 17 November 1501,[3] for which he required a papal dispensation since he was only twenty-one years old (1502, 1511–14 and 1534–39).

The Pope dispensed François from the age defect, and allowed him to retain the benefices which he had already accumulated.

[7] He was named Bishop of Senez in 1508, upon the resignation of Cardinal Nicholas Fieschi, who held the bishopric as Administrator.

His successor, Bishop Jean Baptiste de Laigne d'Oraison was confirmed on 19 September 1509.

[8] Cardinal de Castelnau served as Ambassador of King Louis XII of France to Pope Julius II beginning in 1507.

During the War of the League of Cambrai he was too forthcoming in his exchanges with the Pope on behalf of France and its King, and on 29 June 1510,[10] when he demanded his passport, the Pope, in a fit of anger by no means becoming his high office, sent Cardinal de Castelnau instead to detention in the Castel S.

Shortly thereafter, after swearing not to adhere to the Conciliabulum of Pisa, he was given his passport and allowed to return to France.

On 12 November a delegation of Roman gentlemen appeared at the gate of the Conclave and exhorted the Cardinals to get on with their business and elect a pope.

Rather than see that happen, Colonna and his followers joined the faction of Cardinal de'Medici and elected him pope.

[21] Cardinal François Guillaume de Castelnau-Clermont-Lodève died in Avignon, where he was an Apostolic Legate in March 1541, perhaps on the 13th.