During the late 19th century, most of the mainline Protestant churches struggled to cope with the rise of modernism (which favored adaptation to modern views and trends) along with scientific naturalism, higher biblical criticism, and spiritual apathy. Hundreds of thousands of evangelicals left the large denominations, forming smaller churches to combat the sins of the age.

The vast majority of evangelicals, however, stayed with the mainline and tried to purify their churches from within. By the early 1910s, they formed a massive, cross-denominational movement for reform based on a common acclamation of the "fundamental," or cardinal, doctrines of Christianity.

The most popular list was "The Five Point Deliverance" of the Northern Presbyterians. The 1910 Presbyterian General Assembly ruled that all who wanted to be ordained within their ranks had to affirm the Westminster Confession and subscribe to five fundamental doctrines: 1) the inspiration and inerrancy of the Bible, 2) the virgin birth of Christ, 3) the substitutionary atonement of Christ, 4) the bodily resurrection of Christ, and 5) the historicity of the biblical miracles.

At roughly the same time, A. C. Dixon, R. A. Torrey, and several other luminaries published 12 volumes of essays called The Fundamentals: A Testimony to the Truth (1910-1915). The books, which were mailed to ministers and missionaries around the world, opposed all kinds of modernism, from higher biblical criticism to theological liberalism, from naturalism to Darwinism to democratic socialism. Building on the momentum of the Northern Presbyterians, they rallied people from different Protestant traditions to a least-common-denominator flag of orthodoxy.

By the late 1910s, the conservatives entrenched along the Protestant mainline were poised for battle in defense of the fundamentals. The interdenominational World Christian Fundamentals Association (WCFA), heavily influenced by premillennial dispensationalism, gathered conservatives for whom mainline apostasy was a sign of the coming great tribulation. With eschatological urgency, it reinforced the resolve of anxious evangelical leaders "to contend for the faith that was once for all entrusted to the saints" (Jude 3). In a 1920 editorial published in his Northern Baptist paper, the Rev. Curtis Lee Laws referred to these evangelicals (himself among them) as "fundamentalists." He deemed the name a badge of honor.

During the early 1920s, battles ensued in nearly every mainline Protestant body between the fundamentalists and those who wanted to remain "tolerant" and "open-minded" in response to modern learning. The fundamentalists were defeated in almost every case. They lost control of the mainline and its varied ministries. They lost control of mainline colleges and theological seminaries. Most of them withdrew, forming their own separate ministries. Many began to advocate "second degree separation"—separation not only from sin, worldliness, and apostasy, but also from other Christians standing too close to these things themselves.

Nothing symbolized their defeat more powerfully than the Scopes Monkey Trial held in Dayton, Tennessee, in the summer of 1925. A high school teacher named John T. Scopes was solicited by the fledgling American Civil Liberties Union to test his state's new law against the teaching of evolution. Celebrity lawyer Clarence Darrow was retained for his defense. The prosecution's legal team included William Jennings Bryan, a Presbyterian and famous politician. Fundamentalists won the case (at least temporarily), but they were ridiculed by Darrow and the press. Despite their intellectual rigor and strength in northern urban areas, the fundamentalists have been portrayed ever since as country bumpkins.