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Schlier  was the son of a military doctor and attended the High School-Gymnasium in Landau and Ingolstadt, participated in World War I and in 1919 studied Evangelical Theology at the University of Marburg, Leipzig and Jena. From 1927, he served as pastor and teacher of the New Testament in Halle, Saxony-Anhalt and Wuppertal. From 1935 Schlier was part of the confessing Church and, after the closing of the seminary in Wuppertal he became pastor of the local community of the Confessing Church. (The confessing Church (German language Bekennende Kirche BK) was an opposition movement which arose in the context of the Evangelical German Church against the attempt of the German Nazi regime to align the teaching and the organisation of the Evangelical Church to Nazism. )
After the end of World War II Schlier was again called to the Chair of New Testament and the Early History of Christianity at the Theological Faculty of Bonn University. Over the years however he increasingly moved away from Protestantism, since he concluded, that the Ecclesiological paradigms of the New Testament are anchored in the clearest way to Roman Catholicism. Consequently Schlier in 1952 took a sabbatical and a year later he converted to Catholicism. Concurrently he converted his pupil Uta Ranke-Heinemann, and in 1954 obtained a degree in Catholic theology at Monaco.
Schlier was unable to obtain a professorship at the Faculty of Catholic Theology, since this was then reserved only for consecrated priests. Instead he became an Honorary Professor at the Faculty of Philosophy of the University of Bonn and was an active theological writer. Pope Paul VI called him to be in the Pontifical Biblical Commission.
In addition, Schlier participated in the preparation of an official translation of the Bible and published it together with the Jesuit theologian Karl Rahner as series Quaestiones sentences . Schlier is counted among the leading scholars of the new testament of the 20th century.