It was used a very long time because it was the main road connecting northern Italy, Dauphiné and Avignon, where the popes had settled in the 14th century, for more than 4 centuries by many pilgrims, merchants, and bankers who crossed through Montgenèvre to reach Italy. During the 15th century, the lock of Orpierre, obligatory gateway, has been secured by fortifications with three doors closing the enclosure, which allowed to shelter not only the "House of the Prince" but also the Grand Rue with its Renaissance houses, its Jewish quarter, the Boureynaud, seat of the banking place.
The most famous of these princes of Orange, William I of Nassau, allied in the 16th century, during the Wars of Religion, with the French Protestants when he took the lead of the uprising of the Great Netherlands (which included Holland, Belgium and a part of the North of France) against Philip II of Spain, who wanted to restrict the rights acquired by the old charters, to better fight Protestantism. The village of Orpierre during the 16th century resisted Richelieu then Louis XIV under the protection of the Princes of Orange. It was an isolated Protestant stronghold in the Dauphiné.
Later, the religion wars marked the beginning of its decline; the castles and fortifications that protected this road were dismantled by order of Richelieu around 1633.
Orpierre was sold back to France in 1713 under the Treaty of Utrecht.