Moving into French service in France, he served as a diplomat in securing Charles IX's marriage to Elisabeth de Hapsburg in 1563.

In 1565 he secured the unusual appointment as lieutenant-general of the Lyonnais, granting him military powers over the province and administrative in the absence of the governor.

Birague was among the council that decided on the plan to liquidate the Protestant leadership in a pre-emptive strike, which would spiral out of control into the Massacre of Saint Bartholomew in 1572.

During the interregnum between Charles' death and the return of Henri to the kingdom, Birague led the regency council for Catherine de Medici.

In 1578 Birague was relieved of the seals of the Chancellorship in favour of Philippe Hurault de Cheverny, though he would remain chancellor in a technical capacity until his death.

To support him in this strategic office, Birague took charge of the civil administration of those areas under French control, while Vimercato provided local military leadership.

[2] As the crisis of the civil wars deepened with the fall of many major towns to the Protestant rebels, it was decided that it would serve the crowns interests well to secure the friendship of the duke of Savoy.

[2] In 1565, Birague was elevated to the position of lieutenant-general of the Lyonnais, giving him authority over the military situation in the province and the powers of governor in the absence of Jacques, Duke of Nemours.

[9] At the outbreak of the second war of religion, he mobilised the Catholic notables of Lyon to provide a forced loan to defend the town against an attempted Protestant seizure.

[12] His policy of conciliation and tolerance of Protestantism increasingly falling out of favour, Michel de l'Hôpital surrendered the seals of the chancellorship in September 1568, unwilling to use them to renew the civil wars.

[14] Morvillier in turn returned the seals in 1570, disgusted at the king's willingness to release the duke of Lorraine from the fealty he owed the crown of France for the Duchy of Bar.

[5] Birague was selected by Catherine to play an important role in the negotiations for a marriage between Marguerite de Valois and Navarre.

The marriage was intended by Catherine as a cornerstone of the reconciliation envision by the Peace of Saint-Germain-en-Laye which had brought the third war of religion to a close, uniting the Bourbon's with the Valois.

[17] Birague and Foix were also tasked with conducting preliminary negotiations with England for an anti-Spanish alliance, while this did result in the Treaty of Blois in May 1572, it would not lead to a combined war against Spain.

With the Italians Catherine, Retz, Birague and Nevers accused of having brought about the civil wars of the past decade as a way of destroying the upper nobility of France.

He proposed to Charles that while it was important to show clemency at times, traitors who threatened the kingdom with ruin such as Marshal Montmorency needed to be treated in the 'manner of Louis XI', i.e. arrested.

The king and his mother were ill inclined to follow this course with such a powerful noble, and he was kept under loose surveillance until their hand was forced by a further attempted conspiracy.

Now locked in the Bastille the crown hoped the threat of a potential execution would keep the duke's brothers who were with a mercenary force in Germany from invading the kingdom.

Damville responded with a series of conditions for his return to loyalty, one of which was that Henri III dismiss the foreigners in his midst, mentioning the Italian Birague and Retz by name as a destructive influence on the kingdom.

Birague reacted with horror to this abdication of France's position in Italy, and refused to put his seals to the decision upon Henri's arrival.

[25] Alençon who had been flirting with joining the Malcontents since the original conspiracy, declared his hand in September 1575 and fled court to put himself at the head of the rebellion.

From Dreux he laid out his manifesto, one component of which was a denunciation of the monopoly on high office enjoyed by Italians, who should be expelled from the kingdom, he mentioned Birague specifically.

[31] Recognising the danger of the situation to the crown's authority, a generous truce was agreed in November, hoping to detach Alençon from the other rebels to whom he provided considerable legitimacy.

Henri, having now secured the loyalty of his brother was open to doing away with the peace that he had felt forced to make, however he required funds to fight a war.

He blamed the poverty of the crown on the irresponsibility of previous administrations, and informed the estates that it was their duty to provide money to allow the king to rebuild the royal army.