Strauss was an early pioneer in the ongoing 'Quest of the Historical Jesus' movement, and his Life of Jesus is one of the few landmarks in the field. The first edition of Strauss' book was published in Germany in 1835, when he was only 27 years old. He focused his attention on battling two theological fronts which were current at the time - the biblical Literalists who believed the miracles in the Gospels were to be taken as literal history, and the Rationalists, who believed that the Gospel miracles were true but could be explained by natural and rational causes. Strauss rejected both camps and, in a historical analysis of the Gospels that was scrupulous and exhaustive, concluded that our knowledge of the Historical Jesus is hopelessly buried under layers of legend and myth.

The price that Strauss paid for publication was high – his book scandalized Europe, and cost him his job as Chair of Theology at the University of Zurich, and ultimately his career. Dozens of books, mostly from Germany, were written in rebuttal. The school of Rationalism died in the 19th century, due in no small part to Strauss' criticism. The school of Literalism that Strauss criticized evolved into Fundamentalism in the early 20th century, which was in large part a reaction to the groundbreaking path started by Strauss and his revolutionary book.

Medical missionary Albert Schweitzer described Strauss' Life of Jesus as, "one of the most perfect things in the whole range of learned literature. In over fourteen hundred pages he has not a superfluous phrase; his analysis descends to the minutest details, but he does not lose his way among them; his style is simple and picturesque, sometimes ironical, but always dignified and distinguished". (Introduction by JoeD)