The institutionalized tribunals that were established in the fifteenth and sixteenth centuries to combat heresies in the Latin Christian Church have their origins in concepts of Roman law that pre-date Christendom itself.

In the first centuries of the Common Era, there arose beside the accusatorial system of Roman justice an inquisitorial (Lat. inquirere, meaning "to inquire") procedure that allowed magistrates to investigate crimes in the absence of formal charges being brought to their attention. The roles of evidence collector, prosecutor and judge could henceforward be combined in the individual magistrate. Concurrent with the expansion of this new practice for both civil and criminal investigations, the use of torture as a means of interrogation and eliciting confessions likewise expanded, from the investigation of treason to other crimes, and from slaves to Roman citizens.

This inquisitorial process was already in place when the Roman Empire converted to Christianity in the fourth century, and Christian emperors from Constantine on employed it to suppress heresy. Although defined in terms of religious belief, heresy was largely viewed as a threat to the social order of Latin Christendom. When required, bishops could assume the role of secular magistrates in carrying out inquisitiones. Procedures were codified and regularized with the issuance of the Corpus Iuris Civilis of Justinian in 534. They remained intact even during the centuries of Germanic invasions and domination which followed the collapse of the Roman Empire, although they were rarely used.

The situation began to change towards the end of the twelfth century after the Holy Roman Emperor Frederick Barbarossa and Pope Alexander III reached an accord reconciling their respective powers in the Peace of Venice. In 1184, Pope Lucius III issued the decretal Ad abolendam, which some have called the "founding charter of the inquisition" since it commanded bishops to take an active role in identifying and prosecuting heresy in their jurisdictions. The explicit identification of heresy with treason and its prosecution according to the norms of Roman law was formalized in 1199 by Pope Innocent III. The foundation of mendicant religious orders, especially the Dominicans, in the early decades of the thirteenth century provided a ready supply of papal inquisitors who could be sent to regions most influenced by heretics. Actions by Pope Gregory IX in the 1230s and the canons issued by the Council of Tarragona in 1242 had the effect of centralizing these functions, and even clarified that heresy was an offense punishable by death; nevertheless, it would not be proper to equate these activities of the medieval church with the institutionalized inquisitions which emerged at the end of the fifteenth century. Indeed their aims were mainly to prevent the overzealous prosecution of heretics by individual bishops and to enforce procedures that were meant to be penitential rather than strictly punitive. Handbooks of such procedures were assembled over time, for example the Directorium Inquisitorum compiled by Nicholas Eymeric, who headed a papal inquisition in the eastern portions of Spain from 1357.

The greatest perceived threats of heresy lay in southern France (Languedoc) and northeastern Spain (Aragon). The chief targets were Cathars (also known as Albigenses), who openly condemned the doctrines and authority of the Latin Church, and to a lesser extent the Waldenses. Yet while King Alfonso X could boast that Jews and Muslims lived peacefully alongside Christians in Spain, economic and natural disasters beginning with the Black Death (1348-49) upset the balance, with the result that Jews came to be increasingly resented due to their roles as tax collectors and financiers. By the end of the century, terrible pogroms left thousands of Jews dead or forced to convert to Christianity. During the fifteenth century the descendants of converted Jews, known as conversos, came under increasing suspicion. The appearance in 1460 of a fanatical treatise by Alfonso de Espina, Fortalitium Fidei, attested to the rising tide of anti-Semitism. Finally in 1478, Ferdinand of Aragon and his wife Isabella, Queen of Castile whose subsequent joint rule over Spanish territories and devotion to their ecclesiastically-minded councilors would earn them the designation Reyes Catolicos, the "Catholic Monarchs" implored Pope Sixtus IV to grant them power to appoint inquisitors to deal with the problem of conversos who practiced Jewish rites in secret. Sixtus IV granted their request, but the first Spanish inquisitors operating in Seville proved so severe that he tried to limit their powers. Yet his efforts were largely unsuccessful, and in 1483 he was further induced to allow the Spanish government to name a Grand Inquisitor and Supreme Council to supervise local inquisitorial tribunals that had been established in Castile, Aragon, Valencia, and Catalonia. That same year, Ferdinand appointed as the first Inquisitor-General the Dominican friar Tomás de Torquemada, whose name ever since has remained a symbol of the cruelty and terror wrought by the institution.

Thus by the time the final edict expelling Jews from Spain was issued in 1492, the Spanish Inquisition was ready to counter any religious deviation from within the Christian community. It adopted for its emblem a verse from Psalm 73: Exurge Domine et judica causam tuam" "Rise Up, O Lord, and Judge Thine Own Cause!" It routinely rounded up heretics for sentencing in elaborate public ceremonies known as autos-da-fé (lit. "acts of faith"). Those who could not be induced to renounce their wrongdoing received sentences ranging from humiliation, to confiscation of property, to physical beatings. The most recalcitrant were turned over to royal authorities who executed sentences of death by burning.

During the course of the sixteenth-century, local inquisitorial tribunals were established throughout the Spanish Empire, including Mexico and Peru. Local tribunals typically consisted of two inquisitors, a legal adviser, constable, a fiscal or prosecutor all drawn from the orders or the clergy and a large number of lay assistants, called familiares ("familiars"), who purchased or obtained their offices through inheritance and who enjoyed exceptional civil privileges.

The Spanish Inquisition was introduced into Sicily (then in league with Spain) in 1517, but efforts to establish it in Naples and Milan were unsuccessful. From the beginning of his reign in 1521, and later with the backing of Charles V of Spain, King João III of Portugal urged the pope to permit the creation of an independent Portuguese Inquisition to deal specifically with threats posed by New Christian Judaizers in his country. The policy of assuming that Jews who had been forced to convert according to an edict pronounced in 1497 would gradually be assimilated into Portuguese Christian society was deemed a failure; the New Christians continued their separated existence and resisted governmental control. Despite their heroic opposition and papal reluctance, a Portuguese Inquisition was established in the mid-1530s. Between its first auto-da-fé held in 1540 and the reduction of its powers in 1760, it is estimated that of some thirty thousand cases tried, nearly 1200 Judaizers were condemned to death and another six hundred were burned in effigy. Though the numbers were smaller, the rate of capital punishment was actually higher by comparison to the Spanish Inquisition and consistently more focused on conversos and crypto-Jews.

Rome meanwhile, recognizing the advantages an institutionalized inquisition could offer its fight against Protestants on the one hand, and wanting still to limit the excesses of the Iberian inquisitions on the other, decided to institute its own. Thus in 1542, as part of larger plan for ecclesiastical reformation, Pope Paul III established the Congregation of the Inquisition, consisting of a commission of six cardinals. That same year the first list of books prohibited due to their doctrinal content or criticism of the Latin Church appeared in Rome. As a result of the Council of Trent, which met in several sessions held between 1545-63, it was superseded by a more comprehensive Index of Prohibited Authors and Books which after 1571 was kept up to date by a separate though related Congregation of the Index.

Under Paul III and his successor Julius III, and under most of the popes thereafter with the exceptions of Paul IV (1555-59), who had served on the Congregation of the Inquisition under Paul III and had in fact pressed for its formation, and Pius V (1566-72), the activity of the Roman Inquisition was relatively restrained; Julius, in fact, ruled that it although it had universal jurisdiction, it should in principle limit its operations to the papal states in Italy. Furthermore, by contrast to the Iberian inquisitions, sentencing was conducted in private rather than in mass public autos. Its sentences also tended to be more lenient, partly because the errors it confronted most often once Protestantism had been contained, namely popular superstition and witchcraft, were regarded as a less severe threat to the social order than large populations of conversos. The Spanish Inquisition was abolished in 1808 by Napoleon’s brother, Joseph Bonaparte, who had been appointed king following the occupation of Spain by French troops. The reformers who eventually liberated Spain from the French in 1813 reinforced the ban, but their actions were overturned the following year when Ferdinand VII was restored to power. The resuscitated Inquisition did not last long, however; it was formally and finally suppressed in 1834.

The Roman Inquisition came to a more gradual, bureaucratic end. In 1908, Pius X renamed it the Congregation of the Holy Office, and a few years later its duties were merged with those of the Congregation of the Index. In 1965 Pope Paul VI reorganized the Holy Office and changed its name to the Sacred Congregation for the Doctrine of the Faith; he eliminated the Index altogether the following year.

Hence nothing of the original form of the inquisitions survives today only their records, their memory and the potent myths which still surround them.