In June 1545, he became joint "tutor and administrator" for his nephew, Charles III, Duke of Lorraine, with his sister-in-law Christina of Denmark.

After seizure of the Three Bishoprics in 1552 by Henry II of France, he was re-appointed as sole regent for his nephew, a position he retained until 1559.

Nomeny was detached from the Bishopric of Metz in 1551 and given to him as a margraviate by Maximilian II, Holy Roman Emperor, in 1567, in right of which he was recognized as an independent, hereditary Prince of the Empire (the House of Lorraine would obtain a full vote in the Imperial Diet in 1736 for Nomeny in compensation for cession of the Duchy of Lorraine to France—in addition to acquisition of the Grand Duchy of Tuscany).

[2] In France, his mother's barony of Mercœur was likewise elevated to the status of a princedom (though not independent of the French crown) in 1563, and raised to a ducal peerage in 1569.

His first marriage, on 1 May 1549 in Brussels, was to Countess Marguerite d'Egmont (1517 – 10 March 1554, Bar-le-Duc),[4] daughter of Count Jean IV of Egmont.