Before 1500, Christians in the West saw urgent need for reform. The church had acquired great wealth, while its people suffered from abuses related to the buying and selling of offices in the church. Clergy and monks gathered money from believers by promoting pilgrimages, the veneration of relics, and the sale of indulgences (remission of penalties for sin). The papacy in the middle ages was often corrupt and sometimes divided, as in the Great Schism of 1378-1418, a period in which the western church was split by rival popes. Significant attempts at reform included the conciliar movement, the Franciscan and Dominican Orders, the Waldenses, and the work of Wycliffe and Huss. In about the year 1450, Johann Gutenberg developed a printing press with moveable type; some years later this new technology helped reformers spread their ideas much more broadly than had been possible before.

Humanism was an early contributor to the Era of Reform. This fourteenth and fifteenth-century intellectual movement took as its slogan the words ad fontes, meaning "to the sources" and sought to return to ancient classical writings. Dissatisfied with medieval scholasticism, some of these scholars sought to recover Scripture in its original languages. Desiderius Erasmus, a Dutch humanist and Catholic advocate of reform, produced a critical edition of the Greek New Testament. Many reformers and biblical scholars used this Greek text rather than the Vulgate, the Latin translation by Jerome that had been a standard since the fifth century. Humanists also criticized abuses in church and society, calling for simple piety and classical learning. The influence of humanism was found across a spectrum of Catholics and Protestants in the Era of Reform. Later on, the Enlightenment carried forward some commitments of humanism.

A very broad range of people were active in the Era of Reform. Many who protested abuses in the church came to be called "Protestant." Most Protestants shared a strong commitment to Scripture alone as the authority for Christian faith and life, and proclaimed a message of justification by grace through faith. There were, however, important differences among them in terms of theology, the sacraments, and strategies for carrying out reforms. Protestants ranged from conservatives, who retained much from medieval Catholicism, to radicals, who completely rejected medieval Catholicism. Some of the more conservative groups (Anglican, Lutheran, and some Reformed) came to be called "magisterial" because magistrates eventually gave them legal status as official or state churches.

In 1517 Martin Luther, a monk, Bible teacher, and theologian in the tradition of Augustine, publicly criticized the sale of indulgences with his Ninety-Five Theses. This, plus his attack on scholasticism, sparked the Protestant Reformation. Luther insisted that where human traditions contradicted Scripture, Scripture alone must be authoritative. Luther's German Bible, theological writings, and practical leadership made him the primary mentor of the Lutheran tradition. Many reformers of other traditions were also inspired by Luther. Philip Melanchthon, Luther's younger colleague, wrote the key Lutheran statement of faith, the Augsburg Confession (1530); this was later collected with other Lutheran confessional statements in the Book of Concord (1580). The Lutheran reform took hold in north central and northeastern Germany, Scandinavia, and much of the Baltic area; the support of princes such as Frederick the Wise was very important. Lutherans are generally identified with the conservative and magisterial reformation. Later on, however, there arose a devotional movement to renew established Lutheranism. This movement was called pietism, and its adherents often suffered persecution.

The Radical Reformation was a cluster of movements that completely rejected medieval Catholicism. Radicals criticized Luther and others for not going far enough with their reforms. The radical Thomas Müntzer, for example, denounced infant baptism, rejected "Scripture alone," and sought to reform society as well as church. Sebastian Franck sought a Christianity free from dogma and based on the inner spark of God's Word within each believer. Some radicals turned to violence by supporting the Peasants' Revolt or the Münster Revolution. Others, like Menno Simons, for whom the Mennonites are named, advocated peaceful measures for reform. Many of the radicals were Anabaptists, which meant re-baptizers. They reserved baptism for adult converts only; they taught that people baptized as infants would have to be re-baptized as adults. The Schleitheim Articles (1527) was an early confession of Anabaptists. Neither the Catholics nor the more conservative Protestants recognized Anabaptists or other radicals as legitimate; hence the radicals suffered great persecution for their beliefs. Numerically small, the Anabaptists had some areas of strength in Switzerland and south Germany. Descendants of the Radical Reformation include Mennonites and Brethren churches. Today many Christians, though not directly descended from the Anabaptists, insist on baptizing only older children and adults.

The Reformed wing of Protestantism began under the leadership of Huldrych Zwingli in Zurich and Martin Bucer in Strasbourg. These reformers stressed disciplined pursuit of the Christian life. The Reformed tradition differed with the Lutherans in the understanding of the Lord's Supper and its practice of Christian community. Their premier theologian was John Calvin, leader of reform of the City of Geneva. Calvin's Institutes of the Christian Religion summarized Reformed theology while demonstrating practical concern for the Christian life. The most influential Reformed confession, however, was Heinrich Bullinger's Second Helvetic Confession, which emphasized the notion of God's covenant with believers. The Reformed churches took hold in Scotland under John Knox, in the Netherlands, certain areas of Switzerland and Germany. In France the Huguenots, French Calvinists, endured great persecution. Reformed theology later animated Puritanism in England and New England.

The Reformation in England took a unique course. In order to secure a male heir to the English throne, King Henry VIII sought to re-marry. First, however, he needed his present marriage annulled. The pope refused, and this led to Henry's 1534 "Act of Supremacy" declaring the King to be the head of the Church of England. After Henry VIII a long period of turbulence ensued as English Catholics and Protestants vied for control. A brief restoration of Catholicism occurred under "Bloody Mary." During her reign (1553-1558) many Protestants were put to death, including Thomas Cranmer, author and editor of The Book of Common Prayer. Exiles fled to Geneva and other centers of reform where they learned Calvinist theology and strategies which they later sought to apply in England. In 1558, Mary died and was succeeded by the moderate Elizabeth I. Under Elizabeth, a conservative reformer, a middle way was sought between Catholicism and Protestantism. This middle way included 1) Episcopal polity which involved governance by bishops supportive of the crown; 2) many elements of Catholic worship which were retained; 3) a mildly Calvinistic theology expressed in the Thirty-nine Articles (1563). The Authorized "King James" Version English Bible of 1611 powerfully shaped the English language for centuries to come. In the eighteenth-century John Wesley led a renewal movement within the Church of England; this movement, called Methodism, may be seen as a late flowering of the Reformation in England.

The Catholic Church vigorously opposed the Protestants and this reaction has long been called the "Counter Reformation." Yet sixteenth-century Catholicism was not merely reactive; it had strong movements which expressed a Catholic Reformation in its own right. First was the Council of Trent (1545-1563), a gathering of bishops and theologians, called by Pope Paul III. This council both rejected Protestant theology and sought to reform many of the abuses which had afflicted the church. Trent strengthened the pope's authority and that of bishops. It affirmed the role of tradition, together with Scripture, as authoritative. A second far-reaching event was the formation of the Society of Jesus (Jesuit Order), by Ignatius of Loyola in 1540. This order sought to combat false teaching, educate people in the Catholic faith, and spread that faith throughout the world. Jesuits soon carried Christianity to many parts of the world. Meanwhile Teresa of Avila and John of the Cross pioneered in spiritual renewal through mysticism. Some Catholic leaders, such as Gasparro Contarini, sought to reunite Protestants and Catholics. But differences over theology, sacraments, authority, and practice proved insurmountable.

The Era of Reform permanently changed Christianity in the West. Reforms, so long needed, were carried out. Though many lamented the fragmentation of the church, this was not the first great division. The Great Schism of 1054 had already separated the Orthodox churches of the East from the Catholics in the West. Now the western church had rival claims to true Christianity. Religious conflicts quickly became political and then military. The devastating Thirty Years War ended in 1648 with the Peace of Westphalia. Exhausted peoples and their leaders began, unevenly, to seek peaceful ways to deal with religious diversity. One strategy was toleration, advocated by the seventeenth-century English philosopher John Locke.

The Era of Reform and its aftermath overlapped with European exploration and colonization of North and South America. Through missionary efforts of Protestants and Catholics, Christianity was to become a global religion.