He served under the lieutenant-general of his native province of Dauphiné, Bertrand de Simiane, baron de Gordes, but when the Huguenots raised troops in Dauphiné Lesdiguières threw in his lot with them, and under his kinsman , whom he succeeded in 1570, distinguished himself in the mountain warfare that followed by his bold yet prudent handling of troops. He fought at the Battle of Jarnac and the Battle of Moncontour, and was a guest at the wedding of Henry III of Navarre (later king of France). Warned of the impending St. Bartholomew's Day massacre he retired hastily to Dauphiné, where he secretly equipped and drilled a determined body of Huguenots, and in 1575, after the execution of Charles du Puy de Montbrun in Grenoble, became the acknowledged leader of the Huguenot resistance in the district with the title of commandant general, confirmed in 1577 by Marshal Doraville, by Henry II, Prince of Condé in 1580, and by Henry of Navarre in 1582.